Imidazole derivative used as antiviral agent and use thereof in preparation of medicament

ABSTRACT

Disclosed are an antiviral compound and a use thereof in the preparation of a medicament for the treatment of virus infections. Specifically, the present invention relates an imidazole derivative for treating respiratory syncytial virus infection.

FIELD OF INVENTION

The present invention relates to an antiviral compound and a use thereofin the preparation of a medicament for the treatment of virusinfections. Specifically, the present invention relates an imidazolederivative for treating respiratory syncytial virus infection.

PRIOR ARTS

Respiratory syncytial virus (RSV) is the main cause for serious lowerrespiratory infection to infants, children, the elderly and those withimpaired immunity. Severe viral infection can cause bronchiolitis orpneumonia which needs hospitalized treatment or lead to death (JAMA,1997, 277, 12). Recently, Ribavirin has been approved for the treatmentof this virus infection, which is a nucleoside analogue administrated inthe form of an intranasal aerosol, with considerable toxicity andcontroversial effects. In addition to Ribavirin, RespiGam and Synagis,respectively, are immunoglobulin and monoclonal antibody whichneutralize RSV. They are two biological agents approved currently forthe prophylactic treatment for children high-risk infected with RSV.RespiGam and Synagis are very expensive and require parenteraladministration.

It has been known that many drugs can be used for the inhibition ofrespiratory syncytial virus (De Clercq, Int. J. Antiviral Agent, 1996,7, 193). Y. Tao et al (EP0058146A1, 1998) discloses an antihistamineagent Cetirizine which displays anti-RSV activity. Both J. Med. Chem.1983, 26, 294 (U.S. Pat. No. 4,324,794, 1982) by Tidwell et al andAntimicrobial Agents and Chemotherapy, 1981, 19, 649 by Dubovi et alreport a series of guanyl compounds as RSV inhibitors. Hsu et al alsodiscloses a series of 6-amino pyrimidones with anti RSV antiviralactivity in U.S. Pat. No. 5,256,668 (1993). Besides, Y. Gluzman et al(AU Patent, AU-A-14, 704, 1997) and P. R. Wyde et al (Antiviral Res.1998, 38, 31) disclose a series of triazine-containing compounds for thetreatment and/or prevention of RSV infection. S. Shigeta et al disclosespyrido[1, 2-a]benzopyrrole and pyrimido[1, 2-a]benzimidazole inAntiviral Chem.&amp; Chemother. 1992, 3, 171. It has been proved thatthese compounds inhibit the replication of orthomyxovirus andparamyxovirus in HeLa cells. It has been reported that di-benzimidazoleswith glycol linking group are also effective nasal virus inhibitor(Roderick et al, J. Med. Chem. 1972, 15, 655). Other structurallyrelated compounds are di-benzimidazoles with antifungal activity (B.Cakir et al, Eczacilik Fak Derg. 1988, 5, 71). Very recently, Yu et alfind a series of benzimidazoles for the treatment and prevention of RSVinfection (WO 00/04900). Moreover, Theodore Nitz also finds a series ofcompounds represented by formula III which inhibit RSV in thedetermination of tissue culture media of Hep-2 cells (WO 99/38508).

Currently, BMS discloses BMS433771, the general structure of which isrepresented by formula (B-I):

Viral discloses a class of compounds in WO2013068769A1, the generalstructure of which is represented by formula (B-II):

AstraZeneca discloses a class of compounds in WO2010103306A1, thegeneral structure of which is represented by formula (B-III):

Although the above-mentioned compounds in prior art can be used for theinhibition of respiratory syncytial virus, an improvement in activityand solubility, etc. is still required.

CONTENT OF THE PRESENT INVENTION

An aim of the present invention is to provide a compound represented byformula (I), (II), (III) or (IV) or a pharmaceutically acceptable saltthereof,

Wherein,

each of A, E, A′, E′, A″, E″, A″′ and E″′ independently represents N oroptionally substituted CH;

each of Y, Y′, Y″ and Y″′ independently represents optionallysubstituted (CH₂)_(p), p is an integer among 0˜3, when p is 0, Y, Y′,Y″, Y″′ represent a single bond just for the linkage;

The dotted line represents a single bond, double bond or no bond, whenthe dotted lines in

represent no bond, the structural unit does not exist;

each of D, D′, D″ and D″′ independently represents C or N, when D, D′,D″ or D″′ is C, the dotted line it connects represents a single bond,when D, D′, D″ or D″′ is N, the dotted line it connects represents nobond;

each of M, W, M′, W′, M″, W″, M″′ and W″′ independently represents H, ahalogen, CN or an optionally substituted substituent selected from thegroup consisting of OH, SH, NH₂, PH₂, a hydrocarbon group and ahetero-hydrocarbon group;

each of R₁, R₁′ and R₁″ is independently selected from H, a halogen, CNor an optionally substituted substituent selected from the groupconsisting of OH, SH, NH₂, PH₂, a hydrocarbon group and ahetero-hydrocarbon group;

R₁″′ represents F, Cl, Br, I, CN, OH, SH, NH₂, a substituent selectedfrom the group consisting of a C₁₋₆ alkyl, a C₂₋₆ alkenyl and a C₂₋₆alkynyl which is unsubstituted or substituted by a halogen or ahydroxyl;

each of m, m′ and m″ is independently selected from 0, 1, 2, 3 or 4;

m″′ is selected from 1, 2, 3 or 4;

each of R₂, R₂′, R₂″ and R₂″′ is independently selected from H, ahalogen, CN or an optionally substituted substituent selected from thegroup consisting of OH, SH, NH₂, PH₂, a hydrocarbon group and ahetero-hydrocarbon group;

each of Z and Z′ independently represents optionally substituted NH,(R₅)_(t)(CH₂)_(q) or (CH₂)_(q) (R₅)_(t), R₅ is selected from C═O, C═S,S(═O), S(═O)₂, O or S, t is 0 or 1, q is 0, 1, 2 or 3, t and q are not 0at the same time;

each of U and V independently represents optionally substituted(NH)_(r1)(R₆)_(r2)(CH₂)_(r3), (R₆)_(r2)(NH)_(r1)(CH₂)_(r3),(CH₂)_(r3)(NH)_(r1)(R₆)_(r2), (NH)_(r1)(CH₂)_(r3)(R₆)_(r2),(R₆)_(r2)(CH₂)_(r3)(NH)_(r1) or (CH₂)_(r3)(R₆)_(r2)(NH)_(r1), R₆ isselected from C═O, C═S, S(═O), S(═O)₂, O or S, each of r₁ and r₃ isindependently selected from 0, 1, 2 or 3, r₂ is 0 or 1, that r₁, r₂ andr₃ are 0 at the same time means that U or V represents a single bondjust for the linkage, and U and V are not a single bond at the sametime;

L represents a heteroatom or a heteroatom group;

each of T′ and T″ independently represents H, a halogen, CN or anoptionally substituted substituent selected from the group consisting ofOH, SH, NH₂, PH₂, a hydrocarbon group and a hetero-hydrocarbon group;

B represents an optionally substituted 3- to 8-membered alicyclichydrocarbon;

each of Q, Q′, Q″ and Q″′ independently represents an optionallysubstituted 5- to 12-membered cyclic hydrocarbon or 5- to 12-memberedheterocyclic hydrocarbon; optionally, the compound or thepharmaceutically acceptable salt thereof contains one or more chiralcenters;

optionally, the structural unit

can be replaced with

optionally, the structural unit

can be replaced with

zero, one or two of T₁₋₄ is selected from N, the rest is selected fromC(R_(t));

one of D₁₋₄ is selected from a single bond or —C(R_(d1))(R_(d2))—,another is selected from —C(R_(d1))(R_(d2))—, —C(═O)N(R_(d3))—,—N(R_(d4))—, —C(═NR_(d5))—, —S(═O)₂N(R_(d6))—, —S(═O) N(R_(d7))—, —O—,—S—, —C(═O)O—, —C(═O)—, —C(═S)—, —S(═O)— or —S(═O)₂—, the remaining twoare selected from —C(R_(d1))(R_(d2))—;

each of R_(t), R_(d1) and R_(d2) is independently selected from H, F,Cl, Br, I, CN, OH, SH, NH₂, CHO, COOH, or selected from the groupconsisting of a C₁₋₁₀ alkyl or a heteroalkyl which is optionallysubstituted by R₀₁, a C₃₋₁₀ cyclic hydrocarbon group or a heterocyclichydrocarbon group, a C₁₋₁₀ alkyl or a heteroalkyl substituted by a C₃₋₁₀cyclic hydrocarbon group or a heterocyclic hydrocarbon group;

R₀₁ is selected from F, Cl, Br, I, CN, OH, SH, NH₂, CHO, COOH, R₀₂;

R₀₂ is selected from a C₁₋₁₀ alkyl, a C₁₋₁₀ alkyl amino, a N,N-bis(C₁₋₁₀alkyl) amino, a C₁₋₁₀ alkoxyl, a C₁₋₁₀ alkyl acyl, a C₁₋₁₀alkoxycarbonyl, a C₁₋₁₀ alkyl sulfonyl, a C₁₋₁₀ alkyl sulfinyl, a C₃₋₁₀cycloalkyl, a C₃₋₁₀ cycloalkyl amino, a C₃₋₁₀ heterocycloalkyl amino, aC₃₋₁₀ cycloalkoxyl, a C₃₋₁₀cycloalkyl acyl, a C₃₋₁₀ cycloalkoxycarbonyl,a C₃₋₁₀ cycloalkyl sulfonyl, a C₃₋₁₀ cycloalkyl sulfinyl;

each of the heteroatom and heteroatom group is independently selectedfrom —C(═O)N(R_(d3))—, —N(R_(d4))—, —C(═NR_(d5))—, —S(═O)₂N(R_(d6))—,—S(═O)N(R_(d7))—, —O—, —S—, ═O, ═S, —C(═O)O—, —C(═O)—, —C(═S)—, —S(═O)—and/or —S(═O)₂—;

each of R_(d3-d7) is independently selected from H, R₀₃;

R₀₃ is selected from a C₁₋₁₀ alkyl, a C₁₋₁₀ alkyl acyl, a C₁₋₁₀alkoxycarbonyl, a C₁₋₁₀ alkyl sulfonyl, a C₁₋₁₀ alkyl sulfinyl, a C₃₋₁₀cycloalkyl, a C₃₋₁₀ cycloalkyl acyl, a C₃₋₁₀ cycloalkoxycarbonyl, aC₃₋₁₀ cycloalkyl sulfonyl, a C₃₋₁₀ cycloalkyl sulfinyl;

R₀₂, R₀₃ are optionally substituted by R₀₀₁;

R₀₀₁ is selected from F, Cl, Br, I, CN, OH, N(CH₃)₂, NH(CH₃), NH₂, CHO,COOH, trifluoromethyl, aminomethyl, hydroxymethyl, methyl, methoxyl,formyl, methoxycarbonyl, methylsulphonyl, methylsulfinyl;

a number of each of R₀₁, R₀₀₁, the heteroatom and the heteroatom groupis independently selected from 0, 1, 2 or 3.

In an embodiment of the present invention, the dotted line represents asingle bond or a double bond, each of M, W, M′, W′, M″, W″, M″′ and W″′independently represents optionally substituted CH₂CH, NH or N.

In an embodiment of the present invention,

do not exist, each of M, W, M′, W′, M″, W″, M″′ and W″′ independentlyrepresents a C₁₋₁₂ hydrocarbon group, a C₁₋₁₂ hetero-hydrocarbon group,a C₁₋₁₂ hydrocarbon-substituting heteroatom group, a C₁₋₁₂ hydrocarbongroup substituted by a C₁₋₁₂ hydrocarbon-substituting heteroatom group,—C₁₋₁₂OH, —C₀₋₁₂COOH, —OC₁₋₁₂COOH, —C₁₋₁₂CN, —C₀₋₁₂C(═O)NH₂,—C₀₋₁₂OC₁₋₁₂, —C₀₋₁₂C(═O) C₁₋₁₂, —C₀₋₁₂C(═O)OC₁₋₁₂, —C₀₋₁₂O(O═)CC₁₋₁₂,—C₀₋₁₂S(═O) C₁₋₁₂ or —C₀₋₁₂S(═O)₂C₁₋₁₂ which is optionally substituted,wherein, the above-mentioned group itself is optionally in the form ofan aromatic ring, a hetero-aromatic ring, a cycloaliphatic ring, ahetero-cycloaliphatic ring, an aliphatic chain and/or a hetero-aliphaticchain, and a number of the aromatic ring, hetero-aromatic ring,cycloaliphatic ring, hetero-cycloaliphatic ring, aliphatic chain and/orhetero-aliphatic chain, the ring-forming atom and the number thereof,the linking form between the rings, or the ring and the chain, or thechains can all be arbitrary under the premise of stability available inchemistry, each of the heteroatom and heteroatom group is independentlyselected from O, S, N, S(═O) and/or S(═O)₂, a number of the heteroatomor heteroatom group can be arbitrary under the premise of stabilityavailable in chemistry.

In an embodiment of the present invention, each of M, W, M′, W′, M″, W″,M″′, W″′ independently represents a C₆₋₁₂ aryl or a heteroaryl or anaryl heteroatomic group, a C₃₋₈ alcyl or a heteroalcyl or an alcylheteroatomic group, a C₁₋₆ alkyl, a C₁₋₆ alkyl heteroatomic group, aC₁₋₆ heteroalkyl, a C₂₋₆ alkenyl or alkynyl, a C₂₋₆ heteroalkenyl orheteroalkynyl, a C₂₋₆ alkenyl heteroatomic group or alkynyl heteroatomicgroup which is unsubstituted or substituted by a halogen or a hydroxylor an amino, each of the heteroatom or heteroatom group is independentlyselected from O, S, N, S(═O) and/or S(═O)₂, a number of the heteroatomor the heteroatom group can be arbitrary under the premise of stabilityavailable in chemistry.

In an embodiment of the present invention, each of M, W, M′, W′, M″, W″,M″′ and W″′ independently represents a phenyl,

a biphenyl, a naphthyl, a cyclopentyl, a furyl, a 3-pyrrolyl, apyrrolidinyl, 1,3-dioxlanyl, a pyrazolyl, a 2-pyrazolinyl, apyrazolidinyl, an imidazolyl, an oxazolyl, a thiazolyl, a 1,2,3-azolyl,a 1,2,3-triazolyl, a 1,2,4-triazolyl, a 1,3,4-thiadiazolyl, a4H-pyranyl, a pyridyl, a piperidyl, a 1,4-dioxanyl, a morpholinyl, apyridazinyl, a pyrimidinyl, a pyrazinyl, a piperazinyl, a1,3,5-trithianyl, a 1,3,5-triazinyl, a benzofuranyl, a benzothiophenyl,an indolyl, a benzimidazolyl, a benzothiazolyl, a purinyl, a quinolinyl,an isoquinolinyl, a cinnolinyl or a quinoxalinyl which is unsubstitutedor substituted by a halogen, a hydroxyl or an amino.

In an embodiment of the present invention, each of M and W independentlyrepresents a methyl or an ethyl which is unsubstituted or substituted bya halogen, a hydroxyl or an amino.

In an embodiment of the present invention, each of Q, Q′, Q″ and Q″′independently represents a structural unit represented by formula (a):

Wherein, each of X_(a), X_(b), X_(c) and X_(d) independently representsN or an optionally substituted CH.

In an embodiment of the present invention, B represents an optionallysubstituted cyclopropyl or cyclobutyl or cyclopentyl or cyclohexyl orsuberyl or cyclooctyl.

In an embodiment of the present invention, the compound or thepharmaceutically acceptable salt thereof has a structure represented byformula (V), (VI), (VII) or (VIII):

Wherein, each of X₁, X₂, X₃, X₄, X₁′, X₂′, X₃′, X₄′, X₁″, X₂″, X₃″, X₄″,X₁″′, X₂′″, X₃″′ and X₄′″ independently represents N or an optionallysubstituted CH;

Optionally, the structural unit

can be replaced with

T₁₋₄, D₁₋₄ are defined as claim 1.

In an embodiment of the present invention, the compound or thepharmaceutically acceptable salt thereof has a structure represented byformula (X):

Wherein,

each of M_(1a), M_(2a), M_(3a), M_(4a) independently represents N or anoptionally substituted CH, and at least one of which is N;

R_(1a) is selected from H, a halogen, CN or an optionally substitutedsubstituent selected from the group consisting of OH, SH, NH₂, PH₂, ahydrocarbon group and a hetero-hydrocarbon group;

m_(a) is selected from 0, 1, 2, 3 or 4;

R_(3a) is selected from H, a halogen, CN or an optionally substitutedsubstituent selected from the group consisting of OH, SH, NH₂, PH₂, ahydrocarbon group and a hetero-hydrocarbon group;

Z_(a) represents optionally substituted NH, (R₅)_(t)(CH₂)_(q) or(CH₂)_(q) (R₅)_(t), R₅ is selected from C═O, C═S, S(═O), S(═O)₂, O or S,t is 0 or 1, q is 0, 1, 2 or 3, t and q are not 0 at the same time;

each of U_(a) and V_(a) independently represents optionally substituted(NH)_(r1)(R₆)_(r2)(CH₂)_(r3), (R₆)_(r2)(NH)_(r1)(CH₂)_(r3),(CH₂)_(r3)(NH)_(r1)(R₆)_(r2), (NH)_(r1)(CH₂)_(r3)(R₆)_(r2),(R₆)_(r2)(CH₂)_(r3)(NH)_(r1) or (CH₂)_(r3)(R₆)_(r2)(NH)_(r1), R₆ isselected from C═O, C═S, S(═O), S(═O)₂, O or S, each of r₁ and r₃ isindependently selected from 0, 1, 2 or 3, r₂ is 0 or 1, that r₁, r₂ andr₃ are 0 at the same time means that U_(a) or V_(a) represents a singlebond just for the linkage, and U_(a) and V_(a) are not a single bond atthe same time;

L_(a) represents a heteroatom or a heteroatom group;

Q_(a) represents an optionally substituted 5- to 12-membered cyclichydrocarbon or 5- to 12-membered heterocyclic hydrocarbon; and

optionally, the compound or the pharmaceutically acceptable salt thereofcontains one or more chiral centers.

In an embodiment of the present invention, the compound or thepharmaceutically acceptable salt thereof has a structure represented byformula (XI):

Wherein, each parameter is defined as 1, 2, 6 or 8.

In an embodiment of the present invention, each of R₁, R₁′, R₁″, R_(t),R_(d1), R_(d2) and R_(1a) is independently selected from F, Cl, Br, I,CN, an optionally substituted NH₂, a C₁₋₆ alkyl which is unsubstitutedor substituted by a halogen or a hydroxyl or an amino, a C₂₋₆ alkenyl oran alkynyl which is unsubstituted or substituted by a halogen or ahydroxyl or an amino.

In an embodiment of the present invention, each of R₁, R₁′, R₁″, R_(t),R_(d1), R_(d2) and R_(1a) is independently selected from F, Cl, Br, I,CN, CF₃, NH₂, CH₃, CH₂NH₂ or CH(NH₂)₂.

In an embodiment of the present invention, R₁″′ is selected from F, Cl,Br, I, CH₃, CF₃, CN, OH, SH or NH₂.

In an embodiment of the present invention, each of R₂, R₂′, R₂″, R₂′″and R_(3a) is independently selected from an optionally substituted—C₁₋₁₀R₃, one or more than one heteroatom or heteroatom group isoptionally inserted into the carbon chain or carbon cycle, wherein,

R₃ is selected from OR₄, H, a halogen, CN, ═O or an optionallysubstituted substituent selected from the group consisting of NH₂, anamide, —COOH and —OS(═O)₂CH₃:

R₄ is selected from an ester of phosphoric acid, a phosphonate, an esterof sulphonic acid, a sulfonate, an ester of sulfinic acid, a sulfinateor H;

the heteroatom or heteroatom group in the carbon chain or carbon cycleis selected from —C(═O)N(R_(d3))—, —N(R_(d4))—, —C(═NR_(d5))—,—S(═O)₂N(R_(d6))—, —S(═O) N(R_(d7))—, —O—, —S—, ═O, ═S, —C(═O)O—,—C(═O)—, —C(═S)—, —S(═O)— and/or —S(═O)₂—, R_(d3-d7) are defined asclaim 1;

preferably, the heteroatom or heteroatom group is selected from O, NH,—S(═O)₂—Si, Si(Me₂) and/or Si(OH).

In an embodiment of the present invention, R₂, R₂′, R₂″, R₂′″, R_(3a)are selected from

C₁₋₆R_(2b),

C₁₋₆ alkyl or

each of h₁₋₅ and f₁₋₃ is independently selected from 0, 1, 2, 3;

each of R_(2a) and R_(2b) is independently selected from CN, OR_(2x),C(═O)R_(2y);

R_(2x) is selected from H, an ester of phosphoric acid, a phosphonate,an ester of sulfonic acid, a sulfonate, an ester of sulfinic acid or asulfinate;

R_(2y) is selected from the group consisting of OH, NH₂ and —OC₁₋₆ whichis optionally substituted by a halogen, a methyl, a trifluoromethyl or amethoxy

R_(2c) is selected from O, S, C═O, C═S, S(═O), S(═O)₂, CR_(2c1)R_(2c2),NR_(2c3);

R_(2d) is selected from N, CR_(2d1);

each of R_(2c1), R_(2c2), R_(2c3) and R_(2d1) is independently selectedfrom H, a halogen, CN or an optionally substituted substituent selectedfrom the group consisting of OH, SH, NH₂, PH₂, a hydrocarbon group and ahetero-hydrocarbon group;

R₄ is selected from an ester of phosphonic acid, a phosphonate, an esterof sulfonic acid, a sulfonate, an ester of sulfinic acid, a sulfinate orH.

In an embodiment of the present invention, R₂ is selected from a C₁₋₆alkyl or a C₂₋₆ alkenyl optionally substituted by 0-3 of halogen, NH₂,CN or OR₄, one of —C(═O)—, —S(═O)— or —S(═O)₂— is optionally insertedinto the carbon chain.

In an embodiment of the present invention, R₂, R₂′, R₂″, R₂″′, R_(3a)are selected from

R₄ is selected from an ester of phosphonic acid, a phosphonate, an esterof sulfonic acid, a sulfonate, an ester of sulfinic acid, a sulfinate orH.

In an embodiment of the present invention, the ester of phosphonic acidor the phosphonate is selected from —P(═O)(OC₂H₅)₂, —P(═O)(ONa)₂ or—P(═O)(OK)₂.

In an embodiment of the present invention, Z, Z′, Z_(a) represent C═O,C═S or an optionally substituted CH₂.

In an embodiment of the present invention, each of U, V, U_(a) and V_(a)independently represents optionally substituted [CH₂, (CH₂)₂, O(CH₂)₂,(CH₂)₂O, NH(C═O), (C═O)NH] or C═O.

In an embodiment of the present invention, L, L_(a) represent O, S, S═O,S(═O)₂ or an optionally substituted NH.

In an embodiment of the present invention, each of T′ and T″ isindependently selected from a C₁₋₆ alkyl which is unsubstituted orsubstituted by a halogen or a hydroxyl or an amino, a C₂₋₆ alkenyl oralkynyl which is unsubstituted or substituted by a halogen or a hydroxyor an amino, a C₁₋₆ alkoxy which is unsubstituted or substituted by ahalogen or a hydroxy or an amino, an optionally substituted NH₂, anoptionally substituted 5- to 12-membered cyclic group or heterocyclicgroup or cycloheteroyl group, the optionally substituted NH₂ issubstituted by a C₁₋₆ alkyl, a C₅₋₈ heterocyclic group, a C₁₋₆ alkylsubstituted by a C₅₋₈ heterocyclic group or a C₁₋₆ alkyl substituted bya C₅₋₈ cycloheteroyl group, NH₂ is substituted by 1 or 2 substituent,the heteroatom or heteroatom group is selected from O, S, N, S(═O) orS(═O)₂.

In an embodiment of the present invention, each of T′ and T″ isindependently selected from CH₃, CH(CH₃)₂, cyclopropyl, OCH₃, OCH(CH₃)₂,N(CH₃)₂, N(CH₂CH₃)₂,

phenyl

which is unsubstituted or substituted by a halogen or a hydroxyl or anamino.

In an embodiment of the present invention, the substituent of A, A′, A″,A′″, E, E′, E″, E′″, Y, Y′, Y″, Y″′, M, W, M′, W′, M″, W″, M″′, W′″, R₁,R₁′, R₁″, R₁″′, R₂, R₂′, R₂″, R₂″′, R₃, Z, Z′, U, V, L, T′, T″, Q, Q′,Q″, Q″′, X₁, X₂, X₃, X₄, X₁′, X₂′, X₃′, X₄′, X₁″, X₂″, X₃″, X₄″, X₁′″,X₂′″, X₃′″, X₄″′, M_(1a), M_(2a), M_(3a), M_(4a), R_(1a), R_(3a), R₃,Z_(a), U_(a), V_(a), L_(a), Q_(a), X_(a), X_(b), X_(c), X_(d) isselected from a halogen, CN, ═O, ═S or an optionally substitutedsubstituent selected from the group consisting of OH, SH, NH₂, PH₂, ahydrocarbon group or a heterohydrocarbon group.

In an embodiment of the present invention, the hydrocarbon group,heterohydrocarbon group are optionally substituted and selected from thegroup consisting of a C₁₋₁₂ hydrocarbon group, a C₁₋₁₂ heterohydrocarbongroup, a C₁₋₁₂ cycloheteroyl group, a C₁₋₁₂ hydrocarbon groupsubstituted by a C₁₋₁₂ cycloheteroyl group, —C₁₋₁₂OH, —C₀₋₁₂COOH,—OC₁₋₁₂COOH, —C₁₋₁₂CN, —C₀₋₁₂C(═O)NH₂, —C₀₋₁₂OC₁₋₁₂, —C₀₋₁₂C(═O) C₁₋₁₂,—C₀₋₁₂C(═O)OC₁₋₁₂, —C₀₋₁₂O(O═)CC₁₋₁₂, —C₀₋₁₂S(═O) C₁₋₁₂ or—C₀₋₁₂S(═O)₂C₁₋₁₂, wherein, the above-mentioned groups themselves areoptionally in the form of an aromatic ring, a hetero-aromatic ring, acycloaliphatic ring, a hetero-cycloaliphatic ring, an aliphatic chainand/or a hetero-aliphatic chain, and a number of the aromatic ring,hetero-aromatic ring, cycloaliphatic ring, hetero-cycloaliphatic ring,aliphatic chain and/or hetero-aliphatic chain, the ring-forming atom andthe number thereof, the linking forms between the rings, the ring andthe chain, or the chains can be arbitrary under the premise of stabilityavailable in chemistry, each of the heteroatom or heteroatom group isindependently selected from O, S, N, S(═O) and/or S(═O)₂, the number ofthe heteroatom or heteroatom group is arbitrary under the premise ofstability available in chemistry.

In an embodiment of the present invention, the substituent forsubstitution is selected from F, Cl, Br, I, CN, OH, SH, NH₂, CHO, COOH,or selected from a C₁₋₁₂ alkyl or a heteroalkyl optionally substitutedby R₀₁, a C₃₋₁₂ cyclic hydrocarbon group or a heterocyclic hydrocarbongroup, a C₁₋₁₂ alkyl or a heteroalkyl substituted by a C₃₋₁₂ cyclichydrocarbon group or a heterocyclic hydrocarbon group;

R₀₁ is selected from F, Cl, Br, I, CN, OH, SH, NH₂, CHO, COOH, R₀₂;

R₀₂ is selected from a C₁₋₁₂ alkyl, a C₁₋₁₂ alkyl amino, a N,N-bis(C₁₋₁₂alkyl) amino, a C₁₋₁₂ alkoxy, a C₁₋₁₂ alkyl acyl, a C₁₋₁₂alkoxycarbonyl, a C₁₋₁₂ alkyl sulfonyl, a C₁₋₁₂ alkyl sulfinyl, a C₃₋₁₂cycloalkyl, a C₃₋₁₂ cycloalkyl amino, a C₃₋₁₂ heterocycloalkyl amino, aC₃₋₁₂ cycloalkoxy, a C₃₋₁₂ cycloalkyl acyl, a C₃₋₁₂ cycloalkoxycarbonyl,a C₃₋₁₂ cycloalkyl sulfonyl, a C₃₋₁₂ cycloalkyl sulfinyl;

each of the heteroatom or heteroatom group is independently selectedfrom —C(═O)N(R_(d3))—, —N(R_(d4))—, —C(═NR_(d5))—, —S(═O)₂N(R_(d6))—,—S(═O)N(R_(d7))—, —O—, —S—, ═O, ═S, —C(═O)O—, —C(═O)—, —C(═S)—, —S(═O)—and/or —S(═O)₂—;

each of R_(d3-d7) is independently selected from H, R₀₃;

R₀₃ is selected from a C₁₋₁₂ alkyl, a C₁₋₁₂ alkyl acyl, a C₁₋₁₂alkoxycarbonyl, a C₁₋₁₂ alkyl sulfonyl, a C₁₋₁₂ alkyl sulfinyl, a C₃₋₁₂cycloalkyl, a C₃₋₁₂ cycloalkyl acyl, a C₃₋₁₂ cycloalkoxycarbonyl, aC₃₋₁₂ cycloalkyl sulfonyl, a C₃₋₁₂ cycloalkyl sulfinyl;

R₀₂, R₀₃ are optionally substituted by R₀₀₁;

R₀₀₁ is selected from F, Cl, Br, I, CN, OH, N(CH₃)₂, NH(CH₃), NH₂, CHO,COOH, trifluoromethyl, aminomethyl, hydroxymethyl, methyl, methoxy,formyl, methoxycarbonyl, methylsulphonyl, methylsulfinyl;

A number of R₀₁, R₀₀₁, the heteroatom or the heteroatom group isindependently selected from 0, 1, 2 or 3.

In an embodiment of the present invention, the substituent forsubstitution is selected from a halogen, OH, SH, NH₂, PH₂, CN, ═O, ═S,CF₃, —OCF₃, —OCH₃.

In an embodiment of the present invention, the substituent in Z, Z′,Z_(a) is selected from a C₁₋₆ alkyl which is unsubstituted orsubstituted by a halogen or a hydroxyl or an amino, a C₂₋₆ alkenyl oralkynyl which is unsubstituted or substituted by a halogen or a hydroxylor an amino, an optionally substituted NH₂, an optionally substituted 5-to 12-membered cyclic group or heterocyclic group, the substituent inNH₂ is selected from a C₁₋₆ alkyl, a C₅₋₈ heterocyclic group, a C₁₋₆alkyl substituted by a C₅₋₈ heterocyclic group or a C₁₋₆ alkylsubstituted by a C₅₋₈ cycloheteroyl group, a number of the substituentin NH₂ is 1 or 2, the heteroatom or heteroatom group is selected from O,S, N, S(═O) or S(═O)₂.

In an embodiment of the present invention, the substituent in Z, Z′,Z_(a) is selected from CF₃,

a number of the substituent is 1 or 2.

In an embodiment of the present invention, the substituent in L, L_(a)is selected from a C₁₋₆ alkyl which is unsubstituted or substituted by ahalogen or a hydroxyl or an amino, —C(═O)OC₁₋₆ alkyl, —C(═O)Oalkylenebenzene, —C(═O) C₁₋₆ alkyl, —S(═O)₂C₁₋₆ alkyl, a C₁₋₆ cycloalkylor a C₁₋₆ heterocycloalkyl, —S(═O)₂C₃₋₅ cycloalkyl, —C(═O)C₃₋₅cycloalkyl, —C(═O)OC₃₋₆ cycloalkyl, —CHO, the heteroatom is selectedfrom O, S or N, a number of the heteroatom is 1 or 2.

In an embodiment of the present invention,

the substituent in L, L_(a) is selected from a methyl, —C(═O)OC(CH₃)₃,—C(═O)OCH(CH₃)₂, a benzyloxycarbonyl, —C(═O)CH(CH₃)₂, —S(═O)₂CH₃,

Another aim of the present invention is to provide a compoundrepresented by formula (IX) or a pharmaceutically acceptable saltthereof,

Wherein,

R₇ is selected from —R_(8a)OR_(8b),

R_(8a) is selected from a —C₁₋₁₀ hydrocarbon group optionallysubstituted by a halogen, a methyl, a trifluoromethyl or a methoxyl;

R_(8b) is selected from an ester of phosphonic acid, a phosphonate, anester of sulfonic acid, a sulfonate, an ester of sulfinic acid or asulfinate;

each of j₁₋₅ is independently selected from 0, 1, 2, 3;

R₉ is selected from CN, OR_(9a), C(═O)R_(9b);

R_(9a) is selected from H, an ester of phosphonic acid, a phosphonate,an ester of sulfonic acid, a sulfonate, an ester of sulfinic acid or asulfinate;

R_(9b) is selected from H, a substituent selected from the groupconsisting of OH, NH₂ or —OC₁₋₆ which is optionally substituted by ahalogen, a methyl, a trifluoromethyl or a methoxyl;

R₄ is selected from an ester of phosphonic acid, a phosphonate, an esterof sulfonic acid, a sulfonate, an ester of sulfinic acid, a sulfinate orH.

In an embodiment of the present invention, R_(8a) is selected from

In an embodiment of the present invention, the structural unit

is selected from

In an embodiment of the present invention, the structural unit

is selected from

In an embodiment of the present invention, R_(8b) or R_(9a) is selectedfrom —P(═O)(OC₂H₅)₂, —P(═O)(ONa)₂ or —P(═O)(OK)₂.

The following embodiments are preferred in the present invention:

-   62) Isopropyl    1′-((1-(4-hydroxybutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate;-   63)    1′-((1-(4-Hydroxybutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[cyclopropane-1,3′-indoline]-2′-one;-   64) Isopropyl    1′-((1-(4,4-difluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate;-   65) Isopropyl    2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate;-   66) Isopropyl    2′-oxo-1′-((1-(2,2,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate;-   67) Isopropyl    1′-((1-(2,2-difluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate;-   68) Isopropyl    1′-((1-(3-methyl-2-oxobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate;-   69) Isopropyl    1′-((1-(2,2-difluoro-3-methylbutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate;-   70) (Z)-isopropyl    1′-((1-(2-fluoro-3-methylbut-1-en-1-yl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate;-   71) Isopropyl    1′-((1-(2-fluoro-3-methylbut-2-en-1-yl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate;-   72) Ethyl    1′-((1-isopentyl-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate;-   73) Ethyl    1′-((1-(3-fluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate;-   74) Ethyl    1′-((1-(3-cyanopropyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate;-   75) Ethyl    2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate;-   76) Ethyl 1′-((1-(3-(methyl    sulfonyl)propyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate;-   77) Cyclopentyl    1′-((1-(3-hydroxybutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate;-   78) Isopropyl    5′-bromo-1′-((1-(4-hydroxybutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate;-   79) Isopropyl    5′-bromo-2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate;-   80) Isopropyl    5′-chloro-2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate;-   81) Isopropyl    6′-chloro-2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate;-   82) Isopropyl    6′-fluoro-2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate;-   83) Ethyl    6′-fluoro-2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate;-   84)    1-(Cyclopropanecarbonyl)-6′-fluoro-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one;-   85) Isopropyl    4′-chloro-1′-((1-(4-hydroxybutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate;-   86) Isopropyl    4′-chloro-2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate;-   87) Ethyl    2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-1′,2′-dihydrospiro[azetidine-3,3′-pyrrolo[2,3-c]pyridine]-1-carboxylate;-   88) Isopropyl    2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-1′,2′-dihydrospiro[azetidine-3,3′-pyrrolo[2,3-c]pyridine]-1-carboxylate;-   89)    1-(Cyclopropanecarbonyl)-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-pyrrolo[2,3-c]pyridine]-2′(1′H)-one;-   90)    2′-Oxo-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carbaldehyde;-   91)    1-(1-Methylcyclopropanecarbonyl)-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-pyrrole[2,3-c]pyridine]-2′-one;-   92)    1-Acetyl-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one;-   93)    1-(Cyclopropanecarbonyl)-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one;-   94)    1-Propionyl-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one;-   95)    1-Isobutyryl-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one;-   96)    1-(2,2-Difluoroacetyl)-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one;-   97) 1-(Methyl    sulfonyl)-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one;-   98)    1-(Cyclopropylsulfonyl)-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one;-   99)    1-(Isopropylsulfonyl)-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one;-   100) 1′-((1-(4-hydroxybutyl)-4,    5-dimethyl-1H-imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate;-   101) Ethyl    1′-((4,5-diethyl-1-(4-hydroxybutyl)-1H-imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate;-   102) Isopropyl    2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-1,4,5,6-tetrahydrocyclopenta[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate;-   103) Isopropyl    1′-((1-(4-hydroxybutyl)-1,4,5,6-tetrahydrocyclopenta[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate;-   104) Ethyl    2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-1,4,5,6-tetrahydrocyclopenta[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate;-   105)    1-Isobutyryl-1′-((1-(4,4,4-trifluorobutyl)-1,4,5,6-tetrahydrocyclopenta[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one;-   106) 1-(Methyl    sulfonyl)-1′-((1-(4,4,4-trifluorobutyl)-1,4,5,6-tetrahydrocyclopenta[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one;-   107) Isopropyl    1′-((1-(but-3-en-1-yl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-6′-chloro-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate;-   108) Isopropyl    2′-oxo-1′-((7-oxo-1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate;-   109) Isopropyl    1′-((7-hydroxy-1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate;-   110) Ethyl    1′-((4-methyl-1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate;

Optionally, the above-mentioned compound or the pharmaceuticallyacceptable salt thereof contains one or more chiral centers.

Another aim of the present invention is to provide a pharmaceuticalcomposition, which comprises a therapeutically effective amount of theabove-mentioned compound or the pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier.

Another aim of the present invention is to provide a use of theabove-mentioned compound or the pharmaceutically acceptable salt or thepharmaceutical composition thereof in manufacturing a medicament fortreating respiratory syncytial virus infection.

When R₄ is selected from an ester of phosphonic acid, a phosphonate, anester of sulfonic acid, a sulfonate, an ester of sulfinic acid and asulfinate, the corresponding structure represents a prodrug, the watersolubility of which is greatly improved so as to be suitable forintravenous or intramuscular injection.

C₁₋₁₂ is selected from C₁, C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁ andC₁₂; C₃₋₁₂ is selected from C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁ andC₁₂.

The C₁₋₁₂ alkyl or heteroalkyl, C₃₋₁₂ cyclic group or heterocyclichydrocarbon group, a C₁₋₁₂ alkyl or heteroalkyl substituted by a C₃₋₁₂cyclic hydrocarbon group or heterocyclic hydrocarbon group includes butnot limited to:

a C₁₋₁₂ alkyl, a C₁₋₁₂ alkyl amino, a N,N-bis(C₁₋₁₂ alkyl) amino, aC₁₋₁₂ alkoxyl, a C₁₋₁₂ alkyl acyl, a C₁₋₁₂ alkoxycarbonyl, a C₁₋₁₂ alkylsulfonyl, a C₁₋₁₂ alkyl sulfinyl, a C₃₋₁₂ cycloalkyl, a C₃₋₁₂ cycloalkylamino, a C₃₋₁₂ heterocycloalkyl amino, a C₃₋₁₂ cycloalkoxy, a C₃₋₁₂cycloalkyl acyl, a C₃₋₁₂ cycloalkoxycarbonyl, a C₃₋₁₂ cycloalkylsulfonyl, a C₃₋₁₂ cycloalkyl sulfinyl;

a methyl, an ethyl, a n-propyl, an isopropyl, —CH₂C(CH₃)(CH₃)(OH), acyclopropyl, a cyclobutyl, a propyl methylene, a cyclopropionyl, abenzyloxy, a trifluoromethyl, an aminomethyl, a hydroxymethyl, amethoxy, a formyl, a methoxy carbonyl, a methyl sulfonyl, a methylsulfinyl, an ethoxy, an acetyl, an ethyl sulfonyl, an ethoxy carbonyl, adimethylamino, a diethylamino, a dimethyl amino carbonyl, a diethylamino carbonyl;

N(CH₃)₂, NH(CH₃), —CH₂CF₃, —CH₂CH₂CF₃, —CH₂CH₂F, —CH₂CH₂S(═O)₂CH₃,—CH₂CH₂CN,

—CH₂CH(OH)(CH₃)₂, —CH₂CH(F)(CH₃)₂, —CH₂CH₂F, —CH₂CF₃, —CH₂CH₂CF₃,—CH₂CH₂NH₂, —CH₂CH₂OH, —CH₂CH₂OCH₃, —CH₂CH₂CH₂OCH₃, —CH₂CH₂N(CH₃)₂,—S(═O)₂CH₃, —CH₂CH₂S(═O)₂CH₃,

a phenyl, a thiazolyl, a biphenyl, a naphthyl, a cyclopentyl, a furyl, a3-pyrrolinyl, a pyrrolidinyl, a 1,3-dioxanyl, a pyrazolyl, a2-pyrazolinyl, a pyrazolidinyl, an imidazolyl, an oxazolyl, a thiazolyl,a 1,2,3-azolyl, a 1,2,3-triazolyl, a 1,2,4-triazolyl, a1,3,4-thiadiazolyl, a 4H-pyranyl, a pyridyl, a piperidyl, a1,4-dioxanyl, a morpholinyl, a pyridazinyl, a pyrimidinyl, a pyrazinyl,a piperazinyl, a 1,3,5-trithianyl, a 1,3,5-triazinyl, a benzofuranyl, abenzothiophenyl, an indolyl, a benzimidazolyl, a benzothiazolyl, apurinyl, a quinolinyl, an isoquinolinyl, a cinnolinyl or a quinoxalinyl;

Herein, the term “pharmaceutically acceptable” is aimed at thosecompounds, materials, compositions and/or dosage forms, which are withinthe scope of reliable medical judgment and applicable for use in contactwith human and animal tissue but without too much toxicity, irritation,allergic reactions or other problems or complications, also meet thereasonable benefit/risk ratio.

The term “pharmaceutically acceptable salt” refers to the salt of thecompound of the present invention, which is prepared by the compoundwith specific substituent discovered by the present invention andrelatively non-toxic acid or alkali. When the compound of the presentinvention contains a relatively acidic functional group, analkali-addition salt can be obtained by contacting the compound in aneutral form with sufficient amount of alkali in a pure solution orsuitable inert solvent. The pharmaceutically acceptable alkali-additionsalt includes the salt of sodium, potassium, calcium, ammonium, organicammonia or magnesium or the like. When the compound of the presentinvention contains a relatively alkaline functional group, anacid-addition salt can be obtained by contacting the compound in aneutral form with sufficient amount of acid in a pure solution orsuitable inert solvent. Examples of the pharmaceutically acceptableacid-addition salt include a salt of inorganic acid, the inorganic acidincludes such as hydrochloric acid, hydrobromic acid, nitric acid,carbonic acid, bicarbonate, phosphoric acid, hydrogen phosphate,dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydriodic acid,phosphorous acid etc; and salt of organic acid, the organic acidincludes such as acetic acid, propionic acid, isobutyric acid, maleicacid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaricacid, lactic acid, mandelic acid, phthalic acid, phenylsulfonic acid,p-toluene sulfonic acid, citric acid, tartaric acid, methylsulfonic acidand the like; and also includes salt of amino acid (e.g. arginine etc.),and salt of organic acid such as glucuronic acid and the like (see Bergeet al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science 66:1-19 (1977)). Some specific compound of the present invention containsboth alkaline and acidic functional groups so as to be transformed to beany alkali-addition or acid-addition salt.

Preferably, the neutral form of a compound is regenerated by contactinga salt with a base or an acid in a conventional manner and thenseparating the parent compound. The difference between a parent form ofa compound and the various salt forms lies in some physical properties,such as that the solubility in a polar solvent is different.

The “pharmaceutically acceptable salt” in the present invention is thederivatives of the compound of the present invention, wherein, theparent compound is modified by salifying with an acid or an alkali.Examples of the pharmaceutically acceptable salt include but not limitedto: an inorganic acid or organic acid salt of an alkali such as amine,an alkali metal or organic salt of acid radical such as carboxylic acidand so on. The pharmaceutically acceptable salt includes conventionallynon-toxic salts or quaternary ammonium salts of the parent compound,such as a salt formed by a non-toxic inorganic acid or organic acid. Theconventionally non-toxic salt includes but not limited to those saltsderived from inorganic acids and organic acids, the inorganic acids ororganic acids are selected from 2-acetoxybenzoic acid, 2-isethionicacid, acetic acid, ascorbic acid, phenylsulfonic acid, benzoic acid,bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonicacid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid,glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid,hydriodate, hydroxyl, hydroxynaphthoic, isethionic acid, lactic acid,lactose, dodecanesulfonic acid, maleic acid, malic acid, mandelic acid,methanesulfonic acid, nitric acid, oxalic acid, pamoic acid, pantothenicacid, phenylacetic acid, phosphoric acid, polygalacturonan, propionicacid, salicylic acid, stearic acid, folinate acid, succinic acid,aminosulfonic acid, sulfanilic acid, sulphuric acid, tannic acid,tartaric acid and p-toluene sulfonic acid.

The pharmaceutically acceptable salt of the present invention can beprepared by a conventional method with a parent compound containing anacidic or alkaline group. Generally, the preparation method of the saltcomprises that in water or an organic solvent or the mixture of waterand organic solvent, reacting these compounds in forms of free acids oralkalis with stoichiometric amount of proper alkalis or acids. Ingeneral, preferably choose non-aqueous media such as ether, ethylacetate, ethanol, isopropanol or acetonitrile and so on.

Except for the form of salt, there is a form of prodrug for the compoundin the present invention. The prodrug of the compound described in thepresent invention is easily transformed to be the compound of thepresent invention via chemical changes under physiological conditions.Besides, the prodrug can be transformed to be the compound of thepresent invention via chemical or biochemical method in vivoenvironment.

Some compounds of the present invention can exist in the form ofnon-solvate or solvate forms, including hydrate forms. In general, thesolvate form is similar to the non-solvate form, both of which areincluded within the scope of the present invention. Some compounds ofthe present invention can exist in polycrystalline or amorphous form.

Some compounds of the present invention can contain asymmetric carbonatoms (optical center) or double bonds. The racemic isomers,diastereomers, geometric isomers and single isomers are included withinthe scope of the present invention.

The diagrammatic representation of the racemic isomer, the ambiscalemicand scalemic or the enantiopure compound of the present invention isfrom Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise indicated,the absolute configuration of a stereocenter is represented by the wedgeand dashed lines. When the compound of the present invention contains avinyl double bond or other geometric asymmetric center, unless otherwisespecified, E, Z geometric isomers are included. Similarly, alltautomeric forms are included within the scope of the present invention.

The compound of the present invention may exist as a specific geometricor stereoisomeric isomer. The present invention envisages all of thisclass of compounds, including cis- and trans-isomers, (−)- and(+)-antimers, (R)- and (S)-antimers, diastereomers, (D)-isomer,(L)-isomer, as well as racemic mixtures and other mixtures, such asenantiomers- or diastereoisomers-enriched mixtures, all of thesemixtures are within the scope of the present invention. Other asymmetriccarbon atoms may exist in substituents such as in an alkyl. All of theseisomers and their mixtures are included within the scope of the presentinvention.

Optically active (R)- and (S)-isomers, (D)- and (L)-isomers can beprepared by asymmetric synthesis or chiral reagents or otherconventional techniques. If an enantiomer of a compound of the presentinvention are wanted, asymmetric synthesis or derivatization action ofthe chiral auxiliaries can be employed in preparation, in which theresulting diastereomer mixtures are isolated, and the auxiliary groupsare cleaved to provide the pure desired enantiomer. Or, when a moleculecontains an alkaline functional group (such as amino) or an acidicfunctional groups (such as carboxyl), a salt of diastereomer is formedwith an appropriate optical active acid or alkali, and then the pureenantiomer can be recycled after separated by the fractionalcrystallization or chromatography method which is known in the art. Inaddition, the separation of an enantiomer and a diastereomer is usuallyrealized by the chromatographic method, the chromatography methodemploys a chiral stationary phase, and optionally combined with thechemical derivatization method (e.g. an amine generates a carbamate).

One or more atoms constituting the compound of the present invention maycomprise an unnatural proportion of atomic isotopes. For example, thecompound can be labeled by a radioactive isotope, such as tritium (³H),iodine-125 (¹²⁵I) or C-14(¹⁴C). All the variations in the isotopiccomposition of the compound disclosed in the present invention, whetherradioactive or not, are included within the scope of the presentinvention.

The term “a pharmaceutically acceptable carrier” refers to anyformulation or carrier medium which is capable of delivering effectiveamount of the active substance disclosed in the present invention, doesnot interfere with the biological activity of the active substance, andis with no toxic side-effects on host or patient, representative carrierincludes water, oil, vegetables and minerals, cream base, lotion matrix,ointment matrix etc. The matrix comprises a suspension, a viscosityincreaser, transdermal enhancers etc. Their formulation are well knownto the person in cosmetic or topical drug art. Other information aboutthe carrier can refer to Remington: The Science and Practice ofPharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contentof which is incorporated into this article as reference.

The term “excipient” usually refers to a carrier, diluent and/or mediumrequired for the preparation of an effective pharmaceutical composition.

In terms of drug or pharmacological active agent, the term “effectiveamount” or “therapeutically effective amount” refers to enough quantityof the drug or formulation that can achieve desired effects but is withno toxicity. For the oral formulation of the present invention, “aneffective amount” of one active substance in the composition is theamount required to achieve desired effects in combination with anotheractive substance in the composition. The determination of the effectiveamount varies from person to person, which depends on the age and thegeneral situation of the recipient, also on the specific activesubstance. In one case, an appropriate effective amount can bedetermined by the person skilled in the art according to conventionaltests.

The term “active ingredient”, “therapeutic agent”, “active substance” or“active agent” refers to a chemical entity, which can effectively treatdisorder, illness or disease of a target subject.

The term “substituted” refers to one or more hydrogen atoms in aspecific atom optionally substituted by a substituent, including adeuterium and a variant of hydrogen, as long as the valence state of thespecific atom is normal and the compound obtained after substitution isstable. When the substituent is a ketone group (i.e. ═O), it means thattwo hydrogen atoms are substituted. A substitution of ketone group doesnot occur in an aryl. The term “optionally substituted” means that itmay be substituted or not be substituted, unless otherwise specified,the type and number of substituents can be arbitrary under the premiseof stability available in chemistry.

When any parameter (e.g. R) shows an occurrence for more than one timein the composition or structure of the compound, the definition of eachoccurrence is independent. Therefore, for example, if a group issubstituted by 0-2 of R, the group may optionally be substituted by atmost two R, and R has an independent option in each case. In addition,the combination of substituents and/or their variants is allowed only ifsuch a combination will lead to a stable compound.

When bonds of a substituent can be crossly connected to two atoms of aring, the substituent can be bonded to arbitrary atoms in the ring. Whenthe listed substituent does not specify through which atom it isconnected to the general structure formula including the compound thatis not specifically mentioned, the substituent can be bonded through anyof its atoms. The combination of substituents and/or their variants isallowed only if such a combination will lead to a stable compound. Forexample, the structural unit

represents that the connection can occur on any atom in the cyclohexylor cyclic dienyl.

The substituent in alkyl and heteroalkyl group is generally called“alkyl substituent”, which can be selected from but not limited to thegroup consisting of —R′, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′, halogen,—SiR′R″R″′, OC(O)R′, —C(O)R′, —CO₂R′, —C(═O)NR′R″, —OC(O)NR′R″,—NR″C(O)R′, NR′C(O)NR″R″′, —NR″C(O)₂R′, —NR″″′-C(NR′R″R″′)═NR″″,NR″″C(NR′R″)═NR″′, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, NR″SO₂R′, —CN, —NO₂,—N₃, —CH(Ph)₂ and fluoro(C₁-C₄)alkyl, the number of the substituent isbetween 0 and (2m′+1), wherein m′ is the total number of the carbonatoms in the group. R′, R″, R″′, R″″ and R″″′ are independently selectedfrom H, substituted or unsubstituted heteroalkyl, substituted orunsubstituted aryl (e.g. aryl substituted by 1-3 of halogen),substituted or unsubstituted alkyl, alkoxy, thioalkoxy or aralkyl. Whenthe compound of the present invention includes more than one R group,for example, each of the R group is independently selected, as each ofR′, R″, R″′, R″″ and R″″′ group is when more than one of them areincluded. When R′ and R″ are attached to the same nitrogen atom, theycan form 5-, 6-, or 7-membered ring together with the nitrogen atom. Forexample, —NR′R″ includes but not limited to 1-pyrrolidinyl and4-morpholinyl. According to the above discussion on substituent, theperson skilled in the art can understand, the term “alkyl” is intendedto include a group formed by bonding a carbon atom to a non-hydrogengroup, such as a halogenated alkyl (e.g. —CF₃, —CH₂CF₃) and an acyl(e.g. —C(O)CH₃, —C(O)CF₃, C(O)CH₂OCH₃, etc.).

Similar to the substituent in the alkyl group, the substituent in aryland heteroaryl group is generally called “aryl substituent”, which canbe selected from such as —R′, —OR′, —NR′R″, —SR′, -halogen, —SiR′R″R″′,OC(O)R′, —C(O)R′, —CO₂R′, —C(═O)NR′R″, —OC(O)NR′R″, —NR″C(O)R′, NR′C(O)NR″R″′, —NR″C(O)₂R′, —NR″″′—C(NR′R″R′″)═NR″″, NR″″ C(NR′R″)═NR′″,—S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, NR″SO₂R′, —CN, —NO₂, —N₃, —CH(Ph)₂,fluoro(C₁-C₄) alkoxy and fluoro(C₁-C₄)alkyl, etc., a number of thesubstituent ranges from 0 to the total opening valence of the aromaticring; wherein R′, R″, R″′, R″″ and R″″′ are independently and preferablyselected from H, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted aryl andsubstituted or unsubstituted heteroaryl. When the compound of thepresent invention includes more than one R group, for example, each ofthe R group is independently selected, as each of R′, R″, R″′, R″″ andR″″′ group is when more than one of them are included.

Two substituents attached to adjacent atoms in an aryl or a heteroarylring can optionally be substituted by a substituent with a generalformula as -T-C(O)—(CRR′)q-U—, wherein the T and U are independentlyselected from —NR—, —O—, CRR′— or a single bond, q is an integer from 0to 3. As an alternative, two substituents attached to adjacent atoms inan aryl or a heteroaryl ring can optionally be substituted by asubstituent with a general formula as -A (CH₂)r B-, wherein the A and Bare independently selected from —CRR′—, —O—, —NR—, —S—, —S(O)—, S(O)₂—,—S(O)₂NR′— or a single bond, r is an integer from 1 to 4. Optionally, asingle bond in the new ring thereby formed can be replaced by a doublebond. As an alternative, two substituents attached to adjacent atoms inan aryl or a heteroaryl ring can optionally be substituted by asubstituent with a general formula as -A (CH₂)r B-, wherein the s and dare independently selected from an integer from 0 to 3, X is —O—, —NR′,—S—, —S(O)—, —S(O)₂— or —S(O)₂NR′—. The substituent R, R′, R″ and R″′are respectively and preferably selected from hydrogen and substitutedor unsubstituted (C₁-C₆) alkyl.

Unless otherwise specified, the term “halogenated” or “halogen” itselfor as a part of another substituent refers to fluorine, chlorine,bromine or iodine atom. In addition, the term “halogenated alkyl” isintended to include monohalogenated alkyl and polyhalogenated alkyl. Forexample, the term “halogenated (C₁-C₄) alkyl” is intended to include butnot limited to trifluoromethyl, 2, 2, 2-trifluoroethyl, 4-chlorobutyland 3-bromopropyl, etc.

Examples of halogenated alkyl include but not limited to:trifluoromethyl, trichloromethyl, pentafluoroethyl, andpentachloroethyl. The alkoxy represents that the alkyl group with aspecific number of carbon atoms is connected by an oxygen bridge. TheC₁₋₆ alkoxy includes C₁, C₂, C₃, C₄, C₅ and C₆ alkoxy. Examples ofalkoxy include but not limited to: methoxy, ethoxy, n-propoxy,iso-propoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy andS-pentyloxy. The “cycloalkyl” includes saturated cyclic group, such ascyclopropyl, cyclobutyl or cyclopentyl. The 3- to 7-membered cycloalkylincludes C₃, C₄, C₅, C₆ and C₇ cycloalkyl. The “alkenyl” includes linearor branched hydrocarbon chain, wherein any stable sites on the chainexist one or more C—C double bonds, such as vinyl and propenyl.

The term “halo” or “halogen” refers to fluorine, chlorine, bromine andiodine.

Unless otherwise specified, the term “hetero” refers to a heteroatom ora heteroatom group (i.e. a group containing a heteroatom), includingatoms except carbon (C) and hydrogen (H) and groups containing theseheteroatoms, such as including oxygen (O), nitrogen (N), sulfur (S),silicon (Si), germanium (Ge), aluminum (Al), boron (B), —O—, —S—, ═O,═S, —C(═O)O—, —C(═O)—, —C(═S)—, —S(═O), —S(═O)₂—, and optionallysubstituted —C(═O)N(H)—, —N(H)—, —C(═NH)—, —S(═O)₂N(H)— or —S(═O) N(H)—.

Unless otherwise specified, the “ring” refers to substituted orunsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl,heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl orheteroaryl. The ring includes a single ring, a joint ring, a spiro ring,a fused ring or a bridged ring. A number of the atoms in the ring isusually defined as the member of the ring, for example, “5- to7-membered ring” is a ring looped with 5 to 7 atoms. Unless otherwisespecified, the ring optionally contains 1-3 of heteroatoms. Therefore,“5- to 7-membered ring” includes, for example, phenyl pyridine andpiperidinyl; on the other hand, the term “5- to 7-memberedheterocycloalkyl” includes pyridyl and piperidinyl, but does not includephenyl. The term “ring” also includes a ring system containing at leastone ring, wherein each ring is of the above definition independently.

Unless otherwise specified, the term “heterocycle” or “heterocyclicgroup” refers to a stable monocyclic, bicyclic or tricyclic ringcontaining a heteroatom and a heteroatom group, they can be saturated,partially unsaturated or unsaturated (aromatic), they contain carbonatoms and 1, 2, 3 or 4 of heteroatom in the ring which is independentlyselected from the group consisting of N, O and S, wherein any of theheterocycle can be fused to a benzene ring to form a bicyclic ring.Nitrogen and sulfur atoms can be optionally oxidized (i.e., NO andS(O)_(p)). The Nitrogen atom can be substituted or unsubstituted (i.e. Nor NR, wherein R is H or other substituent that has been definedherein). The heterocycle can be attached to the side group of anyheteroatom or carbon atom to form a stable structure. If the formedcompound is stable, the heterocycle described herein can be substitutedon its carbon or nitrogen atom. The nitrogen atom in the heterocycle isoptionally quaternized. As a preferred embodiment of the presentinvention, when the total number of S and O atoms contained in theheterocycle exceeds 1, these heteroatoms are not adjacent to each other.As another preferred embodiment of the present invention, the totalnumber of S and O atoms in the heterocycle is no more than 1. As usedherein, the term “aromatic heterocyclic group” or “heteroaryl” refers toa stable 5-, 6-, 7-membered monocycle or bicycle or 7-, 8-, 9- or10-membered bicyclic heteroaromatic ring, which contains carbon atomsand 1, 2, 3 or 4 of heteroatom in the ring which independently selectedfrom the group consisting of N, O and S. The Nitrogen atom can besubstituted or unsubstituted (i.e. N or NR, wherein R is H or othersubstituent that has been defined herein). Nitrogen and sulfur atoms canbe optionally oxidized (i.e., NO and S(O)_(p)). It is worth noting that,the total number of S and O atoms in the heteroaromatic ring is no morethan 1. Bridged rings are also included in the definition of theheterocycle. When one or more atoms (i.e. C, O, N, or S) are connectedto two nonadjacent carbon atoms or nitrogen atoms, a bridged ring isformed. The preferred bridged ring includes but not limited to: onecarbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms andone carbon-nitrogen group. It is worth noting that, a bridge alwaysconverts a monocyclic ring into a tricyclic ring. In the bridged ring,the substituent in the ring can also locate on the bridge.

Examples of heterocyclic compound include but not limited to: acridinyl,azocinyl, benzimidazolyl, benzofuranyl, benzomercaptofuranyl,benzomercaptophenyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl,benzotriazolyl, benzotetrazolyl, benzoisoxazolyl, benzoisothiazolyl,benzoimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl,chromene, cinnolinyl decahydroquinolyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuranyl, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indoalkenyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isatino group, isobenzofuranyl, pyran,isoindolyl, isoindolinyl, isoindolyl, indolyl, isoquinolyl,isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl,naphthyridinyl, octahydroisoquinolyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, isooxazolyl, hydroxyl indyl, pyrimidyl, phenanthridinyl,phenanthrolinyl, phenazine, phenothiazine, benzopurinyl, phenoxazinyl,phthalazinyl, piperazinyl, piperidyl, oxopiperidinyl, 4-oxopiperidinyl,piperonyl, pteridyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl,pyrazolinyl, pyrazolyl, pyridazinyl, oxazolopyridine, pyridinoimidazole,pyridinothiazole, pyridyl, pyrimidyl, pyrrolidinyl, pyrrolinyl,2H-pyrrolyl, pyrrolyl, pyrazolyl, quinazolinyl, quinolyl,4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuryl,tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazyl,isothiazolylthienyl, thienyl, thiophenoxazolyl, thiophenothiazolyl,thiophenoimidazolyl, thienyl, triazinyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthenyl. Fusedring and spiro ring compound are also included.

Unless otherwise specified, the term “hydrocarbon group” or its specificconcept (such as alkyl, alkenyl, alkynyl, phenyl, etc.) itself or as apart of another substituent represents a linear, branched or cyclichydrocarbon group or a combination thereof, which can be fullysaturated, monocyclic or polycyclic unsaturated, can be monosubstituted,disubstituted or polysubstituted, can be univalent (such as methyl),bivalent (such as methylene) or multivalent (such as methenyl), caninclude bivalent or multivalent atomic groups, with a specified numberof carbon atoms (such as that C₁-C₁₀ refers to having 1˜10 carbonatoms). The term “alkyl” includes but not limited to an aliphatichydrocarbon group and aromatic hydrocarbon group, the aliphatichydrocarbon group includes linear and cyclic structures, specificallyincludes but not limited to alkyl, alkenyl and alkynyl, the aromatichydrocarbon group includes but not limited to 6- to 12-membered aromatichydrocarbon group such as benzene, naphthalene and the like. In someembodiments, the term “alkyl” refers to linear or branched groups ortheir combination, which can be completely saturated, monocyclic orpolycyclic unsaturated, can include divalent and polyvalent groups.Examples of saturated hydrocarbon groups include but not limited tohomologues or isomers of methyl, ethyl, n-propyl, iso-propyl, n-butyl,tert-butyl, iso-butyl, sec-butyl, iso-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropyl methyl, and n-amyl, n-hexyl, n-heptyl, n-octyl andthe like. Unsaturated alkyl has one or more double or triple bond,examples of which includes but not limited to vinyl, 2-propenyl,butenyl, crotyl, 2-isopentenyl, 2-butadienyl, 2,4-(pentadienyl),3-(1,4-pentadienyl), acetenyl, 1- and 3-propinyl, 3-butynyl, and moreadvanced homologues and isomers.

Unless otherwise specified, the term “heterohydrocarbon group” or itsspecific concepts (such as heteroalkyl, heteroalkenyl, heteroalkynyl,heteroaryl, etc.) itself or the term combining with another term refersto a stable linear, branched or cyclic hydrocarbon group or theircombinations, which consists of a certain number of carbon atoms and atleast one heteroatom. In some embodiments, the term “heteroalkyl” itselfor the term combining with another term refers to a stable linear,branched hydrocarbon group or their combinations, which consists of acertain number of carbon atoms and at least one heteroatom. In a typicalembodiment, the heteroatom is selected from the group consisting of B,O, N and S, in which the nitrogen and sulfur atoms are optionallyoxidized, and the nitrogen atom is optionally quaternized. HeteroatomsB, O, N and S can be located in any internal position of theheterohydrocarbon group (including the position where hydrocarbon groupis attached to the rest part of the molecule). Examples include but notlimited to —CH₂—CH₂—O—CH₃, —CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃,—CH₂—S—CH₂—CH₃, —CH₂—CH₂, —S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃,—CH₂—CH═N—OCH₃ and —CH═CH—N(CH₃)—CH₃. At most two heteroatoms areadjacent, such as —CH₂—NH—OCH₃.

The terms “alkoxy”, “alkylamino” and alkylthio” (or thioalkoxy) are theidiomatic expressions, which refers to the alkyl group is attached tothe rest of molecule through an oxygen, an amino, or a sulfur atom,respectively.

Unless otherwise specified, the term “cyclohydrocarbon group”,“heterocyclo hydrocarbon group” or its specific concepts (such as aryl,heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl,heterocyclovinyl, cycloalkynyl, heterocycloalkynyl, etc.) itself or theterm combining with other terms respectively refers to a cyclic“hydrocarbon group”, “heterohydrocarbon group”. In addition, in terms ofheterohydrocarbon group or heterocyclohydrocarbon group (such asheteroalkyl, heterocycloalkyl), heteroatoms can occupy the positionwhere the heterocyclic ring is attached to the rest part of themolecule. Examples of the cycloalkyl include but not limited tocyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyletc. Unrestricted examples of the heterocyclic group include1-(1,2,5,6-tetrahydropyridinyl), 1-piperidyl, 2-piperidyl, 3-piperidyl,4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl,tetrahydrofuranylindol-3-yl, tetrahydrothiophene-2-yl,tetrahydrothiophene-3-yl, 1-piperazinyl and 2-piperazinyl.

Unless otherwise specified, the term “aryl” refers to a polyunsaturatedaromatic hydrocarbon substituent, which can be monosubstituted,disubstituted or multisubstituted, can be univalent, bivalent ormultivalent. It can be monocyclic or polycyclic (preferably 1˜3 rings).They fuse together or connect by a covalent linkage. The term“heteroaryl” refers to an aryl (or ring) containing 1˜4 heteroatoms. Inan exemplary embodiment, the heteroatom is selected from the groupconsisting of B, N, O, and S, in which the nitrogen and sulfur atoms areoptionally oxidized, and the nitrogen atom is optionally quaternized.The heteroaryl group can be connected to the rest part of the moleculevia a heteroatom. Unrestricted examples of an aryl or a heteroarylinclude phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl,2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl,pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl,3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl,5-thiazolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-pyridyl,3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl,purinyl, 2-benzoimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl,2-quinoxalyl, 5-quinoxalyl, 3-quinolyl and 6-quinolyl. Any one of thesubstituents in the aryl and heteroaryl ring system is selected from theacceptable substituents described below.

For the sake of briefness, when used in combination with other terms(e.g. aryloxy, arylthio, aralkyl), the aryl includes the definition ofaryl and heteroaryl ring defined above. Therefore, the term “aralkyl” isintended to include the groups that aryl attached to alkyl (e.g. benzyl,phenyl ethyl, pyridyl methyl), including those alkyls wherein carbonatoms (such as methylene) has been replaced by such as oxygen atoms,such as phenoxy methyl, 2-pyridyloxymethyl-3-(1-naphthoxy) propyl, etc.

The term “leaving group” refers to a functional group or atom which canbe replaced by another functional group or atom through a substitutionreaction (e.g., nucleophilic substitution reaction). For example,representative leaving groups include triflate; chlorine, bromine,iodine; sulfonate, such as mesylate, tosylate, p-bromobenzene sulfonate,p-tosylate etc.; acyloxy, such as acetoxy, trifluoroacetoxy and so on.

The term “protecting group” includes but not limited to “the protectinggroup of an amino”, “the protecting group of a hydroxyl”, or “theprotecting group of a mercapto”. The term “the protecting group of anamino” refers to a protecting group that is suitable for preventing sidereactions occur at the nitrogen atom of an amino group. A representativeprotecting group of an amino includes but not limited to: formyl; acyl,such as alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl);alkoxycarbonyl, such as tert-butoxycarbonyl (Boc); aryl methoxycarbonyl,such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc);aryl methyl, such as benzyl (Bn), triphenyl methyl (Tr),1,1-bis-(4′-methoxyphenyl) methyl; silyl, such as trimethylsilyl (TMS)and tert-butyldimethylsilyl (TBS) and etc. The term “the protectinggroup of a hydroxyl” refers to a protecting group that is suitable forpreventing side reactions of a hydroxyl group. A representativeprotecting group of a hydroxyl includes but not limited to: alkyl, suchas methyl, ethyl, and tert-butyl; acyl, such as alkanoyl (such asacetyl); aryl methyl, such as benzyl (Bn), p-methoxybenzyl (PMB),9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl,such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS) and etc.

The compound of the present invention can be prepared through manysynthetic methods which are well-known to the person skilled in the art,including the specific embodiments listed below and its combination withother chemical synthetic methods and the equivalent alternative methodswhich are known to the person skilled in the art, the preferredembodiments include but not limited to the embodiments of the presentinvention.

Unless otherwise specified, an eluting system of the columnchromatography and a developing system of the thin-layer chromatographyused for purifying the compound includes: A: a system of dichloromethaneand methanol, B: a system of petroleum ether and ethyl acetate, C: asystem of dichloromethane and acetone. A ratio of the solvent volume isregulated according to the polarity of the compound, which also can beregulated by adding a small amount of alkaline or acidic reagent such astriethylamine and acetic acid etc.

The present invention adopts the following abbreviations: aq representswater; HATU represents2-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate; EDC represents N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride; m-CPBA represents m-chloroperbenzoic acid;eq represents equivalent, equal-quantitative; CDI represents carbonyldiimidazole; DCM represents dichloromethane; PE represents petroleumether; DIAD represents diisopropyl azodicarboxylate; DMF representsN,N-dimethylformamide; DMSO represents dimethylsulfoxide; EtOAcrepresents ethyl acetate; EtOH represents ethanol; MeOH representsmethanol; Cbz represents benzyloxycarbonyl, a protecting group of anamino; Boc represents tert-butoxycarbonyl, a protecting group of anamine; HOAc represents acetic acid; NaCNBH₃ represents sodiumcyanoborohydride; r.t. represents room temperature; O/N representsovernight; THF represents tetrahydrofuran; Boc₂O representsdi-tert-butyl dicarbonate; TFA represents trifluoroacetic acid; DIPEArepresents diisopropylethyl amine; SOCl₂ represents thionyl chloride;CS₂ represents carbon disulfide; TsOH represents p-toluene sulfonicacid; NFSI represents N-fluorobenzenesulfonimide; NCS representsN-chlorosuccinimide; n-Bu4NF represents tetrabutylammonium fluoride;iPrOH represents 2-propanol; mp represents melting point; LDA representslithium diisopropylamide; PE represents petroleum ether; PMB representsp-methoxybenzyl; AIBN represents 2,2′-azo bisisobutyronitrile;i-Pr-PEPPSI represents [1,3-bis(2,6-diisopropylbenzyl) imidazolyl-2-ene(3-chloropyridinyl)]palladium chloride.

Compounds are named by manual work or software ChemDraw®, commerciallyavailable compounds are named in accordance with suppliers' catalogue.

The compound of the present invention is of high efficiency, lowtoxicity, and is remarkable in activity, solubility and pharmacokineticsetc., the druggability of which is good, and is more suitable for themanufacture of pharmaceuticals.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

The following examples further illustrate the present invention, but itdoes not mean any unfavorable limitation to the present invention. Theapplication has already described the present invention in details, inwhich the embodiments also have been disclosed, therefore, it is obviousfor the person skilled in the art to vary and improve the embodiments ofthe present invention without departing from the spirit and scope of thepresent invention.

Reference 1 tert-Butyl2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate

Step 1 tert-Butyl 3-((2-bromophenyl)carbamoyl)azetidine-1-carboxylate

1-(tert-Butoxycarbonyl)azetidine-3-carboxylic acid (5.85 g, 29.07 mmol)was dissolved in 50 mL THF, N,N′-carbonyldiimidazole (4.95 g, 30.52mmol) was then added at r.t., stirring at reflux for 90 min.2-Bromoaniline (5.0 g, 29.07 mmol) was then added at r.t., stirring atreflux for 12 h, the reaction mixture was concentrated under reducedpressure to obtain the crude, 300 mL water was added, extracted with EA(200 mL×2), organic phases were combined and washed in sequence withwater (200 mL×2), saturated sodium chloride solution (200 mL×2), driedover anhydrous sodium sulfate, filtered, the filtrate was concentratedunder reduced pressure, the residue was purified by silica gel columnchromatography with eluting system B to obtain tert-butyl3-((2-bromophenyl)carbamoyl)azetidine-1-carboxylate (5 g, colorlessoil), yield: 48.4%.

¹H NMR (400 MHz, CDCl₃), δ 8.35 (d, J=7.9 Hz, 1H), 7.66 (br. s., 1H),7.55 (d, J=7.9 Hz, 1H), 7.34 (t, J=7.7 Hz, 1H), 7.02 (t, J=7.5 Hz, 1H),4.29-4.14 (m, 4H), 3.46-3.34 (m, 1H), 1.46 (s, 9H).

Step 2 tert-Butyl3-((2-bromophenyl)(4-methoxybenzyl)carbamoyl)azetidine-1-carboxylate

tert-Butyl 3-((2-bromophenyl)carbamoyl)azetidine-1-carboxylate (5 g,14.08 mmol) was dissolved in 50 mL anhydrous DMF, 60% sodium hydride(0.676 g, 16.89 mmol) was added under ice-bath condition, stirring for0.5 h under nitrogen gas atmosphere, then 4-methoxybenzyl chloride (2.42g, 15.48 mmol) was added, the reaction mixture was stirred for 2 h atr.t. 300 mL water was added into the reaction mixture, extracted with EA(200 mL×2), organic phases were combined and washed in sequence withwater (200 mL×3), saturated sodium chloride solution (200 mL×2), driedover anhydrous sodium sulfate, filtered, the filtrate was concentratedunder reduced pressure, the residue was purified by silica gel columnchromatography with eluting system B to obtain tert-butyl3-((2-bromophenyl)(4-methoxybenzyl)carbamoyl)azetidine-1-carboxylate(6.5 g, colorless oil), yield: 97.2%.

¹H NMR (400 MHz, CDCl₃) δ 7.69 (dd, J=1.9, 7.7 Hz, 1H), 7.25-7.16 (m,2H), 7.10 (d, J=8.5 Hz, 2H), 6.79 (d, J=8.8 Hz, 2H), 6.65 (dd, J=2.0,7.3 Hz, 1H), 5.56 (d, J=14.1 Hz, 1H), 4.29 (br. s., 1H), 4.00 (d, J=14.3Hz, 2H), 3.79 (s, 3H), 3.72 (br. s., 1H), 3.56 (br. s., 1H), 3.10-3.01(m, 1H), 1.41 (s, 9H).

Step 3 tert-Butyl1′-(4-methoxybenzyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate

tert-Butyl3-((2-bromophenyl)(4-methoxybenzyl)carbamoyl)azetidine-1-carboxylate(1.63 g, 3.42 mmol) was dissolved in 5 mL anhydrous toluene, Pd catalysti-Pr-PEPPSI9 (163 mg, CAS: 905459-27-0) and sodium tert-butoxide (493mg, 5.13 mmol) were added, stirring for 0.5 h under 110° C. microwave.100 mL water was added into the reaction mixture, extracted with EA (100mL×2), organic phases were combined and washed in sequence with water(100 mL×3), saturated sodium chloride solution (100 mL×2), dried overanhydrous sodium sulfate, filtered, the filtrate was concentrated underreduced pressure, the residue was purified by silica gel columnchromatography with eluting system B to obtain tert-butyl1′-(4-methoxybenzyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate(3.7 g, colorless oil), yield: 68.6%.

¹H NMR (400 MHz, CDCl₃) δ 7.59 (d, J=7.3 Hz, 1H), 7.32-7.26 (m, 3H),7.15 (t, J=8.0 Hz, 1H), 6.89 (d, J=8.5 Hz, 2H), 6.82 (d, J=7.8 Hz, 1H),4.89 (s, 2H), 4.47 (d, J=8.3 Hz, 2H), 4.13 (d, J=8.0 Hz, 2H), 3.82 (s,3H), 1.55 (s, 9H).

Step 4 tert-Butyl 2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate

tert-Butyl1′-(4-methoxybenzyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate(3.68 g, 9.34 mmol) was dissolved in 108 mL acetonitrile and 36 mLwater, ammonium ceric nitrate (20.47 g, 37.36 mmol) was added, stirringfor 2 h at r.t. 100 mL water was added into the reaction mixture,extracted with EA (100 mL×2), organic phases were combined and washed insequence with water (100 mL×3), saturated sodium chloride solution (100mL×2), dried over anhydrous sodium sulfate, filtered, the filtrate wasconcentrated under reduced pressure, the residue was purified by silicagel column chromatography with eluting system B to obtain tert-butyl2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate (500 mg, yellow oil),yield: 19.5%.

¹H NMR (400 MHz, CDCl₃) δ 7.96 (br. s., 1H), 7.54 (d, J=7.3 Hz, 1H),7.31-7.27 (t, J=8.0 Hz, 1H), 7.18-7.09 (t, J=8.0 Hz, 1H), 6.90 (d, J=7.8Hz, 1H), 4.39 (d, J=8.3 Hz, 2H), 4.11-4.06 (m, 2H), 1.50 (s, 9H).

Reference 2 tert-Butyl1′-(4-methoxybenzyl)-2′-oxo-1′,2′-dihydrospiro[azetidine-3,3′-pyrrolo[2,3-c]pyridine]-1-carboxylate

Step 1 tert-Butyl 3-(fluorocarbonyl)azetidine-1-carboxylate

1-(tert-Butoxycarbonyl)azetidine-3-carboxylic acid (9.74 g, 0.048 mol,1.0 eq.) was dissolved in 100 mL anhydrous DCM, N, N-diethylaminosulfurtrifluoride (11.59 g, 0.072 mol) was added under an ice-bath condition,stirring for 10 h at r.t., the reaction mixture was poured into a mixedsolution of 100 mL ice-water and 100 mL EA, organic phase was washed insequence with ice water (100 mL×3), saturated sodium chloride solution(100 mL×2), dried over anhydrous sodium sulfate, filtered, the filtratewas concentrated under reduced pressure to obtain a crude product oftert-butyl tert-butyl 3-(fluorocarbonyl)azetidine-1-carboxylate (10.82g, colorless oil), which is directly used for the next step.

Step 2 tert-Butyl3-((4-iodopyridin-3-yl)carbamoyl)azetidine-1-carboxylate

4-Iodo-3-aminopyridine (5.0 g, 215 mmol) was dissolved in 40 mLanhydrous DMF, 60% sodium hydride (1.03 g, 430 mmol) was added under anice-bath condition, stirring for 0.5 h under nitrogen gas atmosphere.tert-Butyl 3-(fluorocarbonyl)azetidine-1-carboxylate (6.56 g, 330 mmol)was added into the reaction system, stirring for 10 h at r.t., thereaction mixture was poured into a mixed solution of 100 mL NH₄Claqueous solution and 100 mL EA, organic phase was washed in sequencewith ice-water (70 mL×3), saturated sodium chloride solution (70 mL×2),dried over anhydrous sodium sulfate, filtered, the filtrate wasconcentrated under reduced pressure, the residue was purified by silicagel column chromatography with eluting system B to obtain tert-butyl3-((4-iodopyridin-3-yl)carbamoyl)azetidine-1-carboxylate (5.64 g, lightyellow oil), yield: 64.97%.

¹H NMR (400 MHz, CDCl₃) δ 9.18 (s, 1H), 7.99 (d, J=5.0 Hz, 1H), 7.74 (d,J=5.3 Hz, 1H), 7.61 (br. s., 1H), 4.25-4.13 (m, 4H), 3.49-3.39 (m, 1H),1.43 (s, 9H).

Step 3 tert-Butyl3-((4-iodopyridin-3-yl)(4-methoxybenzyl)carbamoyl)azetidine-1-carboxylate

tert-Butyl 3-((4-iodopyridin-3-yl)carbamoyl)azetidine-1-carboxylate(5.64 g, 139.9 mmol) was dissolved in 20 mL anhydrous DMF, 60% sodiumhydride (436.2 mg, 181.8 mmol) was added under an ice-bath condition,stirring for 0.5 h under nitrogen gas atmosphere. 4-Methoxybenzylchloride (3.27 g, 209.9 mmol) was dripped into the reaction system,stirring for 10 h at r.t., the reaction mixture was poured into a mixedsolution of 100 mL saturated sodium bicarbonate aqueous solution and 100mL EA, organic phase was washed in sequence with ice-water (70 mL×3),saturated sodium chloride solution (70 mL×2), dried over anhydroussodium sulfate, filtered, the filtrate was concentrated under reducedpressure, the residue was purified by silica gel column chromatographywith eluting system B to obtain tert-butyl3-((4-iodopyridin-3-yl)(4-methoxybenzyl)carbamoyl)azetidine-1-carboxylate(4.92 g, yellow oil), yield: 31.86%.

¹H NMR (400 MHz, CDCl₃) δ 8.14-8.13 (d, J=5.2 Hz, 1H), 7.90 (d, J=5.0Hz, 1H), 7.69 (s, 1H), 7.06 (d, J=8.5 Hz, 2H), 6.78 (d, J=8.8 Hz, 2H),5.62-5.54 (m, 1H), 4.30 (t., 1H), 4.00 (t., 1H), 3.94 (d, J=14.3 Hz,1H), 3.77 (s, 3H), 3.73 (m., 1H), 3.59 (t, J=8.4 Hz, 1H), 2.98-2.89 (m,1H), 1.41-1.37 (s, 9H).

Step 4 tert-Butyl1′-(4-methoxybenzyl)-2′-oxo-1′,2′-dihydrospiro[azetidine-3,3′-pyrrolo[2,3-c]pyridine]-1-carboxylate

tert-Butyl3-((4-iodopyridin-3-yl)(4-methoxybenzyl)carbamoyl)azetidine-1-carboxylate(4.2 g, 8.03 mmol) was dissolved in 10 mL anhydrous toluene, sodiumtert-butoxide (1.16 g, 12.05 mmol) and i-Pr-PEPPSI (210 mg) were addedat one time under nitrogen gas atmosphere, the reaction system wasreacted for 40 min under 110° C. microwave, the reaction mixture waspoured into a mixed solution of 80 mL saturated sodium bicarbonateaqueous solution and 80 mL EA, organic phase was washed in sequence withice-water (60 mL×3), saturated sodium chloride solution (60 mL×2), driedover anhydrous sodium sulfate, filtered, the filtrate was concentratedunder reduced pressure, the residue was purified by silica gel columnchromatography with eluting system B to obtain tert-butyl1′-(4-methoxybenzyl)-2′-oxo-1′,2′-dihydrospiro[azetidine-3,3′-pyrrolo[2,3-c]pyridine]-1-carboxylate(2.05 g, yellow oil), yield: 64.8%.

¹H NMR (400 MHz, CDCl₃) δ=8.43 (d, J=4.5 Hz, 1H), 8.13 (s, 1H), 7.50 (d,J=4.5 Hz, 1H), 7.28-7.22 (m, J=8.8 Hz, 2H), 6.85 (d, J=8.5 Hz, 2H), 4.86(s, 2H), 4.44 (d, J=8.3 Hz, 2H), 4.09-4.04 (m, 2H), 3.80-3.75 (m, 3H),1.53-1.46 (m, 9H).

Reference 3 Isopropyl 2′-oxo[azetidine-3,3′-indoline]-1-carboxylate

Step 1 1′-(4-Methoxybenzyl)spiro[azetidine-3,3′-indoline]-2′-one

tert-Butyl1′-(4-methoxybenzyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate(500 mg, 1.27 mmol) was dissolved in 2 mL MeOH, HCl/MeOH (4 N, 2 mL) wasadded at r.t., the reaction mixture was stirred for 1 h at r.t. Thereaction mixture was added with 100 mL saturated sodium carbonatesolution to adjust pH to 9, extracted with EA (100 mL×3), organic phaseswere combined and washed in sequence with water (50 mL×3), saturatedsodium chloride solution (50 mL×2), dried over anhydrous sodium sulfate,filtered, the filtrate was concentrated under reduced pressure to obtain1′-(4-methoxybenzyl)spiro[azetidine-3,3′-indoline]-2′-one (360 mg,yellow oil), which is directly used for the next step withoutpurification.

¹H NMR (400 MHz, DMSO-d6), δ 7.73 (d, J=7.3 Hz, 1H), 7.28-7.17 (m, 3H),7.09 (t, J=8.0 Hz, 1H), 6.94-6.81 (m, 3H), 4.79 (s, 2H), 4.00 (d, J=7.3Hz, 2H), 3.69 (s, 3H), 3.55 (d, J=7.3 Hz, 2H).

Step 2 Isopropyl1′-(4-methoxybenzyl)-2′-oxo[azetidine-3,3′-indoline]-1-carboxylate

1′-(4-Methoxybenzyl)spiro[azetidine-3,3′-indoline]-2′-one (360 mg, 1.22mmol) was dissolved in 4 mL DCM, TEA (371 mg, 3.67 mL) was added atr.t., isopropoxy formyl chloride (164 mg, 1.34 mmol) was added dropwiseunder an ice-bath condition, stirring for 1 h at r.t. The reactionmixture was added with 100 mL water, extracted with DCM (100 mL×3),organic phases were combined and washed in sequence with 1N HCl (100mL×3), saturated sodium carbonate solution (100 mL×2), water (100 mL×2),dried over anhydrous sodium sulfate, filtered, the filtrate wasconcentrated under reduced pressure to obtain isopropyl1′-(4-methoxybenzyl)-2′-oxo[azetidine-3,3′-indoline]-1-carboxylate (460mg, yellow oil), which is directly used for the next step withoutpurification.

¹H NMR (400 MHz, CDCl₃) δ 7.55 (d, J=7.3 Hz, 1H), 7.26-7.19 (m, 3H),7.11 (t, J=8.0 Hz, 1H), 6.85 (d, J=8.5 Hz, 2H), 6.78 (d, J=7.8 Hz, 1H),5.01-4.95 (m, 1H), 4.84 (s, 2H), 4.46 (d, J=8.0 Hz, 2H), 4.13 (d, J=8.0Hz, 2H), 3.78 (s, 3H), 1.29 (d, J=6.3 Hz, 6H).

Step 3 2,6-Dicarboxylic acid pyridine-1-oxide

Pyridine-2,6-dicarboxylic acid (15 g, 89.7 mmol) was added into 50 mLhydrogen peroxide to form a suspension, catalytic amount of sodiumtungstate (975 mg) was added at r.t., the suspension was heated to 100°C. and stirred for 2 h. After cooling to r.t., 103 mL hydrogen peroxidewas added again and the suspension was heated to 100° C. and stirred for18 h. The reaction solution was cooled to 0° C., white crystal wasprecipitated, filtered and the filtrate-cake was washed with ice-waterto obtain 2,6-dicarboxylic acid pyridine-1-oxide (10 g, white solid),yield: 61%.

¹H NMR (400 MHz, CDCl₃) δ 8.73 (d, J=8.0 Hz, 2H), 7.98 (t, J=8.0 Hz,1H).

Step 4 Isopropyl 2′-oxo[azetidine-3,3′-indoline]-1-carboxylate

Isopropyl1′-(4-methoxybenzyl)-2′-oxo[azetidine-3,3′-indoline]-1-carboxylate (350mg, 0.92 mmol) was dissolved in 10.5 mL acetonitrile and 3.5 mL water,ammonium ceric nitrate (3.03 g, 5.52 mmol) and 2,6-dicarboxylic acidpyridine-1-oxide (1.01 g, 5.52 mmol) were added and stirring for 2 h atr.t. Saturated sodium carbonate solution and 100 mL water were added,the mixture was extracted with EA(100 mL×2), organic phases werecombined and washed in sequence with water (100 mL×3), saturated sodiumchloride solution (100 mL×2), dried over anhydrous sodium sulfate,filtered, the filtrate was concentrated under reduced pressure, theresidue was purified by silica gel column chromatography with elutingsystem B to obtain isopropyl2′-oxo[azetidine-3,3′-indoline]-1-carboxylate (70 mg, yellow oil),yield: 29.3%.

¹H NMR (400 MHz, CDCl₃) δ 7.67 (br. s., 1H), 7.55 (d, J=7.5 Hz, 1H),7.32-7.27 (m, 1H), 7.18-7.11 (m, 1H), 6.90 (d, J=8.0 Hz, 1H), 5.03-4.94(m, 1H), 4.43 (d, J=8.0 Hz, 2H), 4.15-4.09 (m, 2H), 1.31-1.26 (d, J=4.0Hz, 6H).

Reference 4 1-Isobutyrylspiro[azetidine-3,3′-indoline]-2′-one

Step 11-Isobutyryl-1′-(4-methoxybenzyl)spiro[azetidine-3,3′-indoline]-2′-one

1′-(4-Methoxybenzyl)spiro[azetidine-3,3′-indoline]-2′-one (800 mg, 2.72mmol) was dissolved in 8 mL DCM, TEA (400 mg, 3.95 mL) was added atr.t., isobutyryl chloride (400 mg, 3.77 mmol) was added dropwise underan ice-bath condition, stirring for 18 h at r.t. The reaction mixturewas added with 100 mL water, extracted with DCM (100 mL×2), organicphases were combined and washed in sequence with 1N HCl (100 mL×3),saturated sodium carbonate solution (100 mL×2), water (100 mL×2), driedover anhydrous sodium sulfate, filtered, the filtrate was concentratedunder reduced pressure, the residue was purified by silica gel columnchromatography with eluting system B to obtain1-isobutyryl-1′-(4-methoxybenzyl)spiro[azetidine-3,3′-indoline]-2′-one(930 mg, yellow oil), yield: 93.9%.

¹H NMR (400 MHz, CDCl₃) δ 7.48 (d, J=7.03 Hz, 1H), 7.21-7.26 (m, 3H),7.08-7.14 (m, 1H), 6.85 (d, J=8.53 Hz, 2H), 6.79 (d, J=7.53 Hz, 1H),4.84 (d, J=2.01 Hz, 2H), 4.62 (d, J=8.03 Hz, 1H), 4.46 (d, J=9.03 Hz,1H), 4.29 (d, J=8.03 Hz, 1H), 4.19 (d, J=9.54 Hz, 1H), 3.75-3.79 (m,3H), 2.53 (td, J=6.96, 13.68 Hz, 1H), 1.19 (d, J=7.03 Hz, 6H).

Step 2 1-Isobutyryl spiro[azetidine-3,3′-indoline]-2′-one

1-Isobutyryl-1′-(4-methoxybenzyl)spiro[azetidine-3,3′-indoline]-2′-one(830 mg, 2.277 mmol) was dissolved in 24 mL acetonitrile and 8 mL water,ammonium ceric nitrate (7.5 g, 13.641 mmol) and 2,6-dicarboxylic acidpyridine-1-oxide (1.6 g, 9.1 mmol) were added and stirring for 2 h atr.t. Saturated sodium carbonate solution and 100 mL water were added,the mixture was extracted with EA (100 mL×2), organic phases werecombined and washed in sequence with water (100 mL×3), saturated sodiumchloride solution (100 mL×2), dried over anhydrous sodium sulfate,filtered, the filtrate was concentrated under reduced pressure, theresidue was purified by silica gel column chromatography with elutingsystem B to obtain 1-isobutyrylspiro[azetidine-3,3′-indoline]-2′-one(100 mg, yellow oil), yield: 18%.

¹H NMR (400 MHz, CDCl₃) δ 8.19 (br. s., 1H), 7.48 (d, J=7.03 Hz, 1H),7.27-7.34 (m, 1H), 7.09-7.18 (m, 1H), 6.93 (d, J=8.03 Hz, 1H), 4.60 (d,J=8.03 Hz, 1H), 4.44 (d, J=9.54 Hz, 1H), 4.29 (d, J=8.03 Hz, 1H), 4.19(d, J=9.54 Hz, 1H), 2.53 (td, J=6.78, 13.55 Hz, 1H), 1.14-1.22 (m, 6H).

Embodiment 62 Isopropyl1′-((1-(4-hydroxybutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate

Step 1 Isopropyl1′-(2,2-diethoxyethyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate

Isopropyl 2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate 62a (1.5 g,5.8 mmol) was dissolved in 15 mL DMF, 2-bromo-1,1-diethoxyethane (1.36g, 7.0 mmol), cesium carbonate (2.5 g, 7.0 mmol), potassium iodide (0.16g, 1.0 mmol) were added, and the reaction solution was heated to 100° C.and stirred for 18 h. The mixture was cooled to r.t., 50 mL water wasadded, extracted with EA (50 mL×3), organic phases were combined andwashed in sequence with water (30 mL×3), saturated sodium chloridesolution (30 mL×2), dried over anhydrous sodium sulfate, filtered, thefiltrate was concentrated under reduced pressure, the residue waspurified by silica gel column chromatography with eluting system C toobtain isopropyl1′-(2,2-diethoxyethyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate62b (1.12 g, colorless oil), yield: 51.4%.

¹H NMR (400 MHz, CD₃OD) δ 7.62 (d, J=7.5 Hz, 1H), 7.38-7.31 (m, 1H),7.18 (t, J=7.5 Hz, 1H), 7.13 (d, J=8.0 Hz, 1H), 5.00-4.90 (m, 1H), 4.77(t, J=5.1 Hz, 1H), 4.31 (d, J=8.3 Hz, 2H), 4.15 (d, J=7.5 Hz, 2H), 3.86(d, J=5.0 Hz, 2H), 3.80-3.70 (m, 2H), 3.59-3.49 (m, 2H), 1.30 (d, J=6.3Hz, 6H), 1.12 (t, J=7.0 Hz, 6H).

Step 2 Isopropyl2′-oxo-1′-(2-oxoethyl)spiro[azetidine-3,3′-indoline]-1-carboxylate

Isopropyl1′-(2,2-diethoxyethyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate62b (0.6 g, 1.6 mmol) was dissolved in 4.5 mL DCM and 1.5 mL water, 4.5mL trifluoroacetic acid was added, stirring for 1 h at r.t. The reactionmixture was adjusted to neutral with saturated potassium carbonateaqueous solution, extracted with DCM (30 mL×3), organic phases werecombined and washed in sequence with water (30 mL×2), saturated sodiumchloride solution (30 mL×2), dried over anhydrous sodium sulfate,filtered, the filtrate was concentrated under reduced pressure to obtainthe crude product of isopropyl2′-oxo-1′-(2-oxoethyl)spiro[azetidine-3,3′-indoline]-1-carboxylate 62c(0.32 g, colorless oil), yield: 66.4%.

Step 3 Isopropyl2′-oxo-1′-((4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate

Isopropyl2′-oxo-1′-(2-oxoethyl)spiro[azetidine-3,3′-indoline]-1-carboxylate 62c(0.32 g, 1.06 mmol) was dissolved in 5 mL anhydrous ethanol,cyclohexane-1,2-dione (0.135 g, 1.2 mmol), ammonium acetate (0.41 g, 5.3mmol) were added, and the reaction mixture was heated to reflux andstirred for 6 h. The reaction mixture was cooled to r.t., 50 mL EA wasadded, then washed with saturated sodium carbonate aqueous solution (30mL×2), dried over anhydrous sodium sulfate, filtered, the filtrate wasconcentrated under reduced pressure, the residue was purified by silicagel column chromatography with eluting system C to obtain isopropyl2′-oxo-1′-((4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate62d (0.38 g, white solid), yield: 91.1%.

¹H NMR (400 MHz, CDCl₃) δ 7.53 (d, J=7.3 Hz, 1H), 7.36-7.30 (m, 1H),7.21 (d, J=7.8 Hz, 1H), 7.18-7.12 (m, 1H), 4.93 (s, 2H), 4.38 (d, J=8.3Hz, 2H), 4.16-4.11 (m, 1H), 4.09 (d, J=8.3 Hz, 2H), 2.51 (br. s., 4H),1.77 (br. s., 4H), 1.28 (d, J=6.3 Hz, 6H).

Step 4 Isopropyl1′-((1-(4-hydroxybutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate

2′-oxo-1′-((4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate62d (0.28 g, 0.71 mmol) was dissolved in 3 mL acetonitrile, 4-bromobutylacetate (0.166 g, 0.85 mmol), potassium carbonate (0.138 g, 1.0 mmol),potassium iodide (0.017 g, 0.1 mmol) were added, the reaction mixturewas heated to reflux and stirred for 18 h. The reaction solution wascooled to r.t., 30 mL water was added, extracted with EA (30 mL×2),organic phases were combined and washed in sequence with water (20mL×2), saturated sodium chloride solution (20 mL×2), dried overanhydrous sodium sulfate, filtered, the filtrate was concentrated underreduced pressure to obtain yellow solid. 3 mL 1M NaOH aqueous solutionwas added to dissolve, stirring for 0.5 h at r.t. The reaction solutionwas added with 30 mL water, extracted with EA (30 mL×2), organic phaseswere combined and washed with saturated sodium chloride solution (20mL×2), dried over anhydrous sodium sulfate, filtered, the filtrate wasconcentrated under reduced pressure, purified with preparative HPLC toobtain the target product isopropyl1′-((1-(4-hydroxybutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate62 (0.1 g, white solid), yield: 35.8%.

MS m/z (ESI): 467.3 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 7.64 (d, J=7.3 Hz, 1H), 7.33-7.25 (m, 1H),7.21-7.15 (m, 1H), 7.05 (d, J=7.8 Hz, 1H), 5.01 (s, 2H), 4.96 (d, J=6.3Hz, 1H), 4.37 (d, J=8.5 Hz, 2H), 4.18 (d, J=8.0 Hz, 2H), 3.99 (t, J=7.5Hz, 2H), 3.57 (t, J=6.1 Hz, 2H), 2.56 (br. s., 2H), 2.49 (br. s., 2H),1.82 (br. s., 4H), 1.72-1.62 (m, 2H), 1.61-1.51 (m, 2H), 1.31 (d, J=6.0Hz, 6H).

Embodiment 631′-((1-(4-Hydroxybutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[cyclopropane-1,3′-indoline]-2′-one

Step 1 1′-(2,2-Dimethoxyethyl)spiro[cyclopropane-1,3′-indoline]-2′-one

Spiro[cyclopropane-1,3′-indoline]-2′-one 63a (3 g, 18.8 mmol) wasdissolved in 3 mL acetonitrile, 2-bromo-1,1-dimethoxyethyl (3.34 g, 19.7mmol), potassium carbonate (12.25 g, 37.6 mmol), potassium iodide (10mg) were added, and the reaction solution was stirred for 16 h at r.t.The reaction solution was concentrated under reduced pressure, 100 mLwater was added, extracted with EA (100 mL×2), organic phases werecombined and washed in sequence with water (100 mL×3), saturated sodiumchloride solution (100 mL×2), dried over anhydrous sodium sulfate,filtered, the filtrate was concentrated under reduced pressure. Columnchromatography (PE:EtOAc=4:1) was used to purify and1′-(2,2-dimethoxyethyl)spiro[cyclopropane-1,3′-indoline]-2′-one 63b (2g, yellow solid) was given, yield: 43.0%.

¹H NMR (400 MHz, CDCl₃) δ 7.25 (d, J=8.0 Hz, 1H), 7.10-7.02 (m, 2H),6.85 (d, J=4.0 Hz, 1H), 4.66 (t, J=5.2 Hz, 1H), 3.93 (d, J=5.6 Hz, 2H),3.43 (d, J=2.4 Hz, 6H), 1.79-1.76 (m, 2H), 1.56-1.53 (m, 2H).

Step 2 2-(2′-Oxospiro[cyclopropane-1,3′-indoline]-1′-yl)acetaldehyde

1′-(2,2-Dimethoxyethyl)spiro[cyclopropane-1,3′-indoline]-2′-one 63b (2g, 8.09 mmol) was dissolved in 3 mL DCM and 1 mL water, 3 mLtrifluoroacetic acid was added at r.t., the reaction solution wasstirred for 2 h at r.t. The reaction solution was concentrated underreduced pressure, 100 mL saturated sodium bicarbonate was added,extracted with EA (100 mL 2), organic phases were combined and washed insequence with saturated sodium bicarbonate solution (100 mL×3),saturated sodium chloride solution (100 mL×2), dried over anhydroussodium sulfate, filtered, the filtrate was concentrated under reducedpressure. Column chromatography (PE:EtOAc=4:1) was used to purify and2-(2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)acetaldehyde 63c (1.5g, white solid) was given, yield: 92.1%.

¹H NMR (400 MHz, CDCl₃) δ 9.74 (s, 1H), 7.26 (t, J=7.9 Hz, 1H), 7.09 (t,J=8.0 Hz, 1H), 6.91 (d, J=8.0 Hz, 1H), 6.76 (d, J=8.0 Hz, 1H), 4.62 (s,2H), 1.86-1.83 (m, 2H), 1.63-1.62 (m, 2H).

Step 31′-((4,5,6,7-Tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[cyclopropane-1,3′-indoline]-2′-one

2-(2′-Oxospiro[cyclopropane-1,3′-indoline]-1′-yl)acetaldehyde 63c (100mg, 0.5 mmol) was dissolved in 3 mL ethanol, cyclohexane-1,2-dione(56.07 mg, 0.5 mmol), ammonium acetate (231 mg, 3.0 mmol) were added atr.t., and the reaction solution was heated to reflux and stirred for 2h. 50 mL water was added into the reaction solution, extracted with EA(50 mL×2), organic phases were combined and washed in sequence withwater (50 mL×3), saturated sodium chloride solution (50 mL×2), driedover anhydrous sodium sulfate, filtered, the filtrate was concentratedunder reduced pressure. Column chromatography (PE:EtOAc=4:1) was used topurify and1′-((4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[cyclopropane-1,3′-indoline]-2′-one63d (77 mg, yellow oil) was given, yield: 52.8%.

¹H NMR (400 MHz, CDCl₃) δ 7.33-7.27 (m, 2H), 7.02 (t, J=7.3 Hz, 1H),6.82 (d, J=7.5 Hz, 1H), 5.01 (s, 2H), 2.59-2.49 (m, 4H), 1.78 (d, J=3.8Hz, 6H), 1.59-1.55 (m, 2H).

Step 41′-((1-(4-Hydroxybutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[cyclopropane-1,3′-indoline]-2′-one

1′-((4,5,6,7-Tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[cyclopropane-1,3′-indoline]-2′-one63d (74 mg, 0.25 mmol) was dissolved in 2 mL acetonitrile, 4-bromobutylacetate (58.53 mg, 0.3 mmol), potassium carbonate (52.52 mg, 0.38 mmol),potassium iodide (4.98 mg, 0.03 mmol) were added at r.t., and thereaction solution was stirred for 12 h at r.t. The reaction solution wasadded with 50 mL water, extracted with EA (50 mL×2), organic phases werecombined and washed in sequence with water (50 mL×3), saturated sodiumchloride solution (50 mL×2), dried over anhydrous sodium sulfate,filtered, the filtrate was concentrated under reduced pressure to obtaincrude product. The crude product was dissolved in 2 mL methanol, NaOH(80 mg) was added at r.t., the reaction solution was stirred for 2 h atr.t. The reaction solution was added with 50 mL water, extracted with EA(50 mL×2), organic phases were combined and washed in sequence withwater (50 mL×3), saturated sodium chloride solution (50 mL×2), driedover anhydrous sodium sulfate, filtered, the filtrate was concentratedunder reduced pressure, preparative HPLC was used to purify and thetarget product1′-((1-(4-hydroxybutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[cyclopropane-1,3′-indoline]-2′-one63 (12.4 mg, white solid), yield: 13.6%.

MS m/z (ESI): 366.2 [M+1]

¹H NMR (400 MHz, METHANOL-d₄) δ 7.21-7.14 (m, 2H), 7.06-7.01 (m, 1H),6.95 (d, J=7.3 Hz, 1H), 5.09 (s, 2H), 3.95-3.88 (m, 2H), 3.48-3.44 (m,2H), 2.56-2.49 (m, 4H), 1.86-1.77 (m, 4H), 1.72-1.63 (m, 4H), 1.53-1.47(m, 4H).

Embodiment 64 Isopropyl1′-((1-(4,4-difluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate

Step 1 Isopropyl2′-oxo-1′-((1-(4-oxobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate

Isopropyl1′-((1-(4-hydroxybutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate64a (0.17 g, 0.36 mmol) was dissolved in 5 mL anhydrous DCM,tetrapropylammonium perruthenate (0.17 g, 0.47 mmol), N-methylmorpholineN-oxide (0.06 g, 0.47 mmol), 4 Å molecular sieves (0.17 g, 0.36 mmol)were added, stirring for 2 h at r.t. The reaction solution was filtered,the filtrate was concentrated under reduced pressure to obtain the crudeproduct of isopropyl2′-oxo-1′-((1-(4-oxobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate64b (0.20 g, dark brown oil).

¹H NMR (400 MHz, CDCl₃) δ 9.78 (s, 1H), 7.56 (m, 2H), 7.32 (t, J=7.60Hz, 1H), 7.14 (t, J=7.60 Hz, 1H), 4.97 (m, 3H), 4.34 (d, J=8.00 Hz, 2H),4.08 (d, J=8.00 Hz, 2H), 3.90 (t, J=8.00 Hz, 2H), 2.58 (m, 4H), 2.48 (m,2H), 1.82-1.60 (m, 6H), 1.27 (d, J=6.00 Hz, 6H).

Step 2 Isopropyl1′-((1-(4,4-difluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate

Isopropyl2′-oxo-1′-((1-(4-oxobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate64b (0.20 g, 0.43 mmol) was dissolved in 2 mL anhydrous DCM,diethylaminosulfur trifluoride (0.22 g, 1.29 mmol) was added at 0° C.,and the reaction mixture was stirred for 16 h at r.t. 50 mL water wasadded, the mixture was extracted with DCM (50 mL×3), organic phases werecombined and washed in sequence with water (50 mL×3), saturated sodiumchloride solution (50 mL×2), dried over anhydrous sodium sulfate,filtered, the filtrate was concentrated under reduced pressure,preparative HPLC was used to purify and the target product isopropyl1′-((1-(4,4-difluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate64 (5 mg, light yellow solid) was given, yield: 2.39%.

MS m/z (ESI): 487.3 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 7.64 (d, J=7.28 Hz, 1H), 7.34-7.25 (m, 1H),7.23-7.15 (m, 1H), 7.08 (d, J=7.78 Hz, 1H), 6.14-5.76 (m, 1H), 5.02 (s,2H), 4.99-4.94 (m, 1H), 4.37 (d, J=8.03 Hz, 2H), 4.17 (d, J=8.03 Hz,2H), 4.03 (t, J=7.65 Hz, 2H), 2.65-2.38 (m, 4H), 2.01-1.64 (m, 8H), 1.31(d, J=6.27 Hz, 6H).

Embodiment 65 Isopropyl2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate

Step 1 Isopropyl2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate

Isopropyl2′-oxo-1′-((4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate65a (0.30 g, 0.76 mmol) was dissolved in 3 mL DMF,4-bromo-1,1,1-trifluorooxybutane (0.17 g, 0.91 mmol) and cesiumcarbonate (0.50 g, 1.52 mmol) were added, stirring for 2 h at 80° C. Thereaction mixture was cooled to r.t., 30 mL water was added, extractedwith EA (30 mL×2), organic phases were combined and washed in sequencewith water (20 mL×2), saturated sodium chloride solution (20 mL×2),dried over anhydrous sodium sulfate, filtered, the filtrate wasconcentrated under reduced pressure, the residue was purified by silicagel column chromatography with eluting system C to obtain the targetproduct isopropyl2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate65 (0.11 g, white solid), yield: 28.7%.

MS m/z (ESI): 505.3 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 7.62 (d, J=7.5 Hz, 1H), 7.29 (t, J=8.0 Hz,1H), 7.17 (t, J=8.0 Hz, 1H), 7.08 (d, J=7.5 Hz, 1H), 4.99 (s, 2H),4.95-4.91 (m, 1H), 4.34 (d, J=8.5 Hz, 2H), 4.15 (d, J=8.0 Hz, 2H), 4.05(t, J=7.8 Hz, 2H), 2.60-2.40 (m, 4H), 2.30-2.19 (m, 2H), 1.93-1.71 (m,6H), 1.29 (d, J=6.0 Hz, 6H).

Embodiment 66 Isopropyl2′-oxo-1′-((1-(2,2,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate

Step 1 1-Bromo-4-hydroxybutan-2-one

4-Hydroxybutanyl 66a (6.00 g, 68.10 mmol) was dissolved in 30 mLmethanol, bromine (10.34 g, 64.70 mmol) was added dropwise at 0° C.,stirring for 2 h at r.t. 30 mL 2N sulphuric acid was added, stirring for12 h at r.t. The reaction mixture was added with 30 mL water, extractedwith DCM/MeOH=10:1 (V/V) (30 mL×3), organic phases were combined andwashed in sequence with water (20 mL×2), saturated sodium chloridesolution (20 mL×2), dried over anhydrous sodium sulfate, filtered, thefiltrate was concentrated under reduced pressure, the residue waspurified by silica gel column chromatography with eluting system C togive 1-bromo-4-hydroxybutan-2-one 66b (2.80 g, yellow oil), yield:24.6%.

¹H NMR (400 MHz, CDCl₃) δ 3.95 (s, 2H), 3.91 (t, J=5.52 Hz, 2H), 2.92(t, J=5.40 Hz, 2H), 2.28 (br. s., 1H).

Step 2 Isopropyl1′-((1-(4-hydroxy-2-oxobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate

Isopropyl2′-oxo-1′-((4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate(0.50 g, 1.27 mmol) was dissolved in 10 mL THF,1-bromo-4-hydroxybutan-2-one 66b (0.42 g, 2.54 mmol) and TEA (0.38 g,3.80 mmol) were added, stirring for 12 h at 70° C. The reaction solutionwas cooled to r.t., 50 mL water was added, extracted with EA (30 mL×3),organic phases were combined and washed in sequence with water (20mL×2), saturated sodium chloride solution (20 mL×2), dried overanhydrous sodium sulfate, filtered, the filtrate was concentrated underreduced pressure, the residue was purified by silica gel columnchromatography with eluting system C to give isopropyl1′-((1-(4-hydroxy-2-oxobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate66c (0.49 g, light yellow solid), yield: 68.3%.

¹H NMR (400 MHz, CDCl₃) δ 7.60 (d, J=7.78 Hz, 1H), 7.50 (d, J=7.03 Hz,1H), 7.32-7.39 (m, 1H), 7.16 (t, J=7.28 Hz, 1H), 4.81-5.04 (m, 5H), 4.30(d, J=8.28 Hz, 2H), 4.08 (d, J=8.28 Hz, 2H), 3.94 (t, J=5.40 Hz, 2H),2.76 (t, J=5.40 Hz, 2H), 2.58 (br. s., 2H), 2.26 (br. s., 2H), 1.85-1.60(m, 4H), 1.22-1.32 (m, 6H).

Step 3 Isopropyl2′-oxo-1′-((1-(2,2,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate

Diethylaminosulfur trifluoride (0.5 mL) was added dropwise intoisopropyl1′-((1-(4-hydroxy-2-oxobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate66c (0.10 g, 0.21 mmol) at 0° C., stirring for 5 h at 50° C. Thereaction mixture was cooled to 0° C., 30 mL water was added, extractedwith DCM (20 mL×3), organic phases were combined and washed in sequencewith water (20 mL×2), saturated sodium chloride solution (20 mL×2),dried over anhydrous sodium sulfate, filtered, the filtrate wasconcentrated under reduced pressure, the residue was purified bypreparative HPLC to give the target product isopropyl2′-oxo-1′-((1-(2,2,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate66 (40 mg, white solid), yield: 36.2%.

MS m/z (ESI): 505.2 [M+1]

¹H NMR (400 MHz, CDCl₃) δ 7.60 (d, J=7.78 Hz, 1H), 7.51 (d, J=7.03 Hz,1H), 7.35 (t, J=7.91 Hz, 1H), 7.15 (t, J=7.28 Hz, 1H), 5.04-4.92 (m,3H), 4.82 (t, J=5.40 Hz, 1H), 4.70 (t, J=5.40 Hz, 1H), 4.49-4.32 (m,4H), 4.09 (d, J=8.53 Hz, 2H), 2.59 (br. s., 2H), 2.51-2.41 (m, 4H), 1.79(br. s., 4H), 1.29 (d, J=6.02 Hz, 6H).

Embodiment 67 Isopropyl1′-((1-(2,2-difluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate

Step 1 Isopropyl2′-oxo-1′-((1-(2-oxobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate

Isopropyl2′-oxo-1′-((4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate67a (0.20 g, 0.51 mmol) was dissolved in 10 mL THF, 1-bromo-2-butanone(0.09 g, 0.61 mmol) and TEA (0.05 g, 0.51 mmol) were added, stirring for12 h at 70° C. The reaction solution was cooled to r.t., 30 mL water wasadded, extracted with EA (20 mL×3), organic phases were combined andwashed in sequence with water (20 mL×2), saturated sodium chloridesolution (20 mL×2), dried over anhydrous sodium sulfate, filtered, thefiltrate was concentrated under reduced pressure, the residue waspurified by silica gel column chromatography with elution system C togive isopropyl2′-oxo-1′-((1-(2-oxobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate67b (0.13 g, light yellow solid), yield: 34.2%.

1H NMR (400 MHz, CDCl₃) δ 7.60 (d, J=8.03 Hz, 1H), 7.50 (d, J=7.28 Hz,1H), 7.35 (t, J=7.53 Hz, 1H), 7.18-7.12 (t, J=7.20 Hz, 1H), 5.00-4.90(m, 5H), 4.29 (d, J=8.28 Hz, 2H), 4.07 (d, J=8.28 Hz, 2H), 2.49-2.66 (m,4H), 2.25 (br. s., 2H), 1.78 (br. s., 4H), 1.28 (d, J=6.27 Hz, 6H), 1.10(t, J=7.28 Hz, 3H).

Step 2 Isopropyl1′-((1-(2,2-difluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate

Diethylaminosulfur trifluoride (0.61 g, 3.78 mmol) was added dropwiseinto isopropyl2′-oxo-1′-((1-(2-oxobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate67b (30 mg, 0.06 mmol) at 0° C., stirring for 5 h at 50° C. The reactionsolution was cooled to 0° C., 30 mL water was added, extracted with DCM(20 mL×3), organic phases were combined and washed in sequence withwater (20 mL×2), saturated sodium chloride solution (20 mL×2), driedover anhydrous sodium sulfate, filtered, the filtrate was concentratedunder reduced pressure, the residue was purified by preparative HPLC togive isopropyl1′-((1-(2,2-difluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate67 (15 mg, light white solid), yield: 46.8%.

MS m/z (ESI): 487.3 [M+1]

¹H NMR (400 MHz, CDCl₃) δ 7.62 (d, J=8.03 Hz, 1H), 7.51 (d, J=7.28 Hz,1H), 7.35 (t, J=7.53 Hz, 1H), 7.15 (t, J=7.53 Hz, 1H), 5.07-4.91 (m,3H), 4.45-4.32 (m, 4H), 4.09 (d, J=8.28 Hz, 2H), 2.59 (br. s., 2H), 2.47(br. s., 2H), 2.11-1.94 (m, 2H), 1.79 (br. s., 4H), 1.28 (d, J=6.27 Hz,6H), 1.13 (t, J=7.53 Hz, 3H).

Embodiment 68 Isopropyl1′-((1-(3-methyl-2-oxobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate

Step 1 Isopropyl1′-((1-(3-methyl-2-oxobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate

Isopropyl2′-oxo-1′-((4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate68a (0.25 g, 0.63 mmol) was dissolved in 10 mL THF,1-bromo-3-methyl-2-butanone (0.21 g, 1.27 mmol) and TEA (0.19 g, 1.90mmol) were added, stirring for 12 h at 70° C. The reaction solution wascooled to r.t., 30 mL water was added, extracted with EA (20 mL×3),organic phases were combined and washed in sequence with water (20mL×2), saturated sodium chloride solution (20 mL×2), dried overanhydrous sodium sulfate, filtered, the filtrate was concentrated underreduced pressure, the residue was purified by silica gel columnchromatography with eluting system C to give the target productisopropyl1′-((1-(3-methyl-2-oxobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate68 (0.21 g, yellow solid), yield: 69.2%.

MS m/z (ESI): 479.4 [M+1]

¹H NMR (400 MHz, CDCl₃) δ 7.61 (d, J=8.03 Hz, 1H), 7.49 (d, J=7.03 Hz,1H), 7.37-7.31 (m, 1H), 7.14 (t, J=7.40 Hz, 1H), 5.01-4.92 (m, 3H), 4.84(s, 2H), 4.31 (d, J=8.28 Hz, 2H), 4.07 (d, J=8.28 Hz, 2H), 2.85-2.75 (m,1H), 2.57 (br. s., 2H), 2.22 (br. s., 2H), 1.77 (br. s., 4H), 1.26 (dd,J=12.80, 6.53 Hz, 12H).

Embodiment 69 Isopropyl1′-((1-(2,2-difluoro-3-methylbutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate

Step 1 Isopropyl1′-((1-(2,2-difluoro-3-methylbutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate

Diethylaminosulfur trifluoride (7.01 g, 43.46 mmol) was added intoisopropyl1′-((1-(3-methyl-2-oxobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate69a (0.26 g, 0.54 mmol), stirring for 1 h at 50° C. The reactionsolution was cooled to 0° C., 80 mL water was added, extracted with DCM(50 mL×3), organic phases were combined and washed in sequence withwater (50 mL×2), saturated sodium chloride solution (50 mL×2), driedover anhydrous sodium sulfate, filtered, the filtrate was concentratedunder reduced pressure, the residue was purified by preparative HPLC togive the target product isopropyl1′-((1-(2,2-difluoro-3-methylbutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate69 (40 mg, white solid), yield: 15.2%.

MS m/z (ESI): 501.3 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 7.61 (d, J=7.5 Hz, 1H), 7.31-7.25 (m, 1H),7.19-7.13 (m, 1H), 7.07 (d, J=7.8 Hz, 1H), 4.98 (s, 2H), 4.94 (d, J=6.5Hz, 1H), 4.53 (t, J=16.3 Hz, 2H), 4.34 (d, J=8.3 Hz, 2H), 4.14 (d, J=8.3Hz, 2H), 2.49 (d, J=19.6 Hz, 4H), 2.31 (td, J=6.9, 14.0 Hz, 1H), 1.79(br. s., 4H), 1.29 (d, J=6.3 Hz, 6H), 1.17 (d, J=6.8 Hz, 6H).

Embodiment 70 Isopropyl(Z)-1′-((1-(2-fluoro-3-methylbut-1-en-1-yl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate

Step 1 Isopropyl(Z)-1′-((1-(2-fluoro-3-methylbut-1-en-1-yl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate

Diethylaminosulfur trifluoride (7.01 g, 43.46 mmol) was added intoisopropyl1′-((1-(3-methyl-2-oxobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate70a (0.26 g, 0.54 mmol), stirring for 1 h at 50° C. The reactionsolution was cooled to 0° C., 80 mL water was added, extracted with DCM(50 mL×3), organic phases were combined and washed in sequence withwater (50 mL×2), saturated sodium chloride solution (50 mL×2), driedover anhydrous sodium sulfate, filtered, the filtrate was concentratedunder reduced pressure, the residue was purified by preparative HPLC togive the target product isopropyl(Z)-1′-((1-(2-fluoro-3-methylbut-1-en-1-yl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate70 (10 mg, white solid), yield: 3.8%.

MS m/z (ESI): 481.3 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 7.61 (d, J=7.3 Hz, 1H), 7.29-7.23 (m, 1H),7.19-7.12 (m, 1H), 6.88 (d, J=7.8 Hz, 1H), 6.20-6.12 (m, 1H), 4.94 (d,J=6.5 Hz, 1H), 4.34 (d, J=8.0 Hz, 2H), 4.15 (d, J=8.0 Hz, 2H), 2.71-2.63(m, 1H), 2.44 (d, J=17.6 Hz, 4H), 1.79 (br. s., 4H), 1.68 (br. s., 1H),1.29 (d, J=6.3 Hz, 6H), 1.24 (d, J=7.0 Hz, 6H).

Embodiment 71 Isopropyl1′-((1-(2-fluoro-3-methylbut-2-en-1-yl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate

Step 1 Isopropyl1′-((1-(2-fluoro-3-methylbut-2-en-1-yl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate

Diethylaminosulfur trifluoride (7.01 g, 43.46 mmol) was added intoisopropyl1′-((1-(3-methyl-2-oxobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate71a (0.26 g, 0.54 mmol), stirring for 1 h at 50′C. The reaction solutionwas cooled to 0° C., 80 mL water was added, extracted with DCM (50mL×3), organic phases were combined and washed in sequence with water(50 mL×2), saturated sodium chloride solution (50 mL×2), dried overanhydrous sodium sulfate, filtered, the filtrate was concentrated underreduced pressure, the residue was purified by preparative HPLC to givethe target product isopropyl1′-((1-(2-fluoro-3-methylbut-2-en-1-yl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate71 (10 mg, white solid), yield: 3.8%.

MS m/z (ESI): 481.4 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 7.61 (d, J=7.5 Hz, 1H), 7.30-7.24 (m, 1H),7.19-7.12 (m, 1H), 7.05 (d, J=7.8 Hz, 1H), 5.01 (s, 2H), 4.95-4.91 (m,3H), 4.32 (d, J=8.3 Hz, 2H), 4.14 (d, J=7.8 Hz, 2H), 2.47 (d, J=4.0 Hz,4H), 1.79 (d, J=2.5 Hz, 7H), 1.64 (d, J=3.0 Hz, 3H), 1.29 (d, J=6.3 Hz,6H).

Embodiment 72 Ethyl1′-((1-isopentyl-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate

Step 1 Ethyl 2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate

tert-Butyl1′-(4-methoxybenzyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate72a (4 g, 10.5 mmol) was dissolved in 40 mL trifluoroacetic acid,stirring for 10 min at r.t., trifluoromethanesulfonic acid (4.731 g,31.54 mmol) was added dropwise at 0° C., stirring for 4 h at r.t. Thereaction solution was concentrated under reduced pressure, 28 mL THF and28 mL water were added into the residue, pH was adjusted to 9-10 withsodium carbonate, ethyl chlorocarbonate (1.90 g, 17.51 mmol) was addeddropwise at 0° C., stirring for 12 h at r.t. 100 mL water was added, themixture was extracted with EA (80 mL×3), organic phases were combinedand washed in sequence with water (80 mL×2), saturated sodium chloridesolution (80 mL×2), dried over anhydrous sodium sulfate, filtered, thefiltrate was concentrated under reduced pressure, the residue waspurified by silica gel column chromatography with eluting system C togive ethyl 2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate 72b (2.4g, yellow solid), yield: 96.0%.

¹H NMR (400 MHz, CDCl₃) δ 8.68 (br. s., 1H), 7.54 (d, J=7.3 Hz, 1H),7.32-7.27 (m, 1H), 7.18-7.10 (t, J=8.0 Hz, 1H), 6.95 (d, J=7.5 Hz, 1H),4.44 (d, J=8.3 Hz, 2H), 4.27-4.09 (m, 4H), 1.30 (t, J=8.0 Hz, 3H).

Step 2 Ethyl1′-(2,2-diethoxyethyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate

Ethyl 2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate 72b (20.0 g,81.2 mmol) was dissolved in 100 mL DMF, 2-bromo-1,1-diethoxyethane (32.0g, 162.4 mmol), cesium carbonate (59.9 g, 183.9 mmol), potassium iodide(1.35 g, 8.13 mmol) were added, stirring for 4 h at 90° C. The reactionmixture was added with 300 mL H₂O, extracted with EA (300 mL×3), organicphases were combined and washed in sequence with water (200 mL×2),saturated sodium chloride solution (200 mL×2), dried over anhydroussodium sulfate, filtered, the filtrate was concentrated under reducedpressure, the residue was purified by silica gel column chromatographywith elution system C to give ethyl1′-(2,2-diethoxyethyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate72c (24.5 g, yellow solid), yield: 74.9%.

¹H NMR (400 MHz, CDCl₃) δ 7.51 (d, J=7.04 Hz, 1H), 7.27-7.33 (m, 1H),7.12 (t, J=7.52 Hz, 1H), 7.04 (d, J=7.52 Hz, 1H), 4.69 (t, J=5.28 Hz,1H), 4.40 (d, J=8.04 Hz, 2H), 4.17 (q, J=7.04 Hz, 2H), 4.07-4.14 (m,2H), 3.82 (d, J=5.52 Hz, 2H), 3.69-3.78 (m, 2H), 3.44-3.55 (m, 2H), 1.28(t, J=7.04 Hz, 3H), 1.13 (t, J=7.03 Hz, 6H).

Step 3 Ethyl2′-oxo-1′-(2-oxoethyl)spiro[azetidine-3,3′-indoline]-1-carboxylate

Ethyl1′-(2,2-diethoxyethyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate72c (10.0 g, 27.59 mmol) was dissolved in 45 mL DCM and 15 mL H₂O,trifluoroacetic acid (68.00 g, 596.39 mmol) was added, stirring for 2 hat r.t., sodium carbonate was used to neutralize, 150 mL H₂O was addedinto the reaction mixture. The mixture was extracted with DCM (150mL×3), organic phases were combined and washed in sequence with water(80 mL×2), saturated sodium chloride solution (80 mL×2), dried overanhydrous sodium sulfate, filtered, the filtrate was concentrated underreduced pressure to give the crude product ethyl2′-oxo-1′-(2-oxoethyl)spiro[azetidine-3,3′-indoline]-1-carboxylate 72d(7.5 g, yellow oil), yield: 94.3%.

Step 4 Ethyl2′-oxo-1′-((4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate

Ethyl 2′-oxo-1′-(2-oxoethyl)spiro[azetidine-3,3′-indoline]-1-carboxylate72d (5.50 g, 19.08 mmol) was dissolved in 50 mL ethanol, ammoniumacetate (7.35 g, 95.40 mmol), 1,2-cyclohexanedione (2.57 g, 22.9 mmol)were added, refluxing for 4 h. The reaction solution was cooled to r.t.,150 mL water was added, extracted with EA (150 mL×3), organic phaseswere combined and washed in sequence with water (100 mL×2), saturatedsodium chloride solution (100 mL×2), dried over anhydrous sodiumsulfate, filtered, the filtrate was concentrated under reduced pressure,the residue was purified by silica gel column chromatography withelution system C to give ethyl2′-oxo-1′-((4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate72e (4.3 g, yellow oil), yield: 59.2%.

MS m/z (ESI): 381.0 [M+1]

Step 5 Ethyl1′-((1-isopentyl-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate

Ethyl2′-oxo-1′-((4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate72e (0.3 g, 0.79 mmol) was dissolved in 10 mL DMSO,1-bromo-3-methylbutane (0.14 g, 0.95 mmol), potassium carbonate (0.33 g,2.37 mmol), potassium iodide (13.09 mg, 0.08 mmol) were added, refluxingfor 5 h. The reaction mixture was cooled to r.t., 30 mL H₂O was added,extracted with EA (30 mL×3), organic phases were combined and washed insequence with water (30 mL×2), saturated sodium chloride solution (30mL×2), dried over anhydrous sodium sulfate, filtered, the filtrate wasconcentrated under reduced pressure, preparative HPLC was used to purifyand ethyl1′-((1-isopentyl-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate72 (43 mg, white solid) was given, yield: 12.0%.

MS m/z (ESI): 451.3 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 7.64 (d, J=7.2 Hz, 1H), 7.22 (d, J=7.2 Hz,1H), 7.19 (d, J=7.6 Hz, 1H), 7.04 (d, J=8.0 Hz, 1H), 5.00 (s, 2H), 4.30(t, J=8.8 Hz, 2H), 4.21 (d, J=7.2 Hz, 4H), 3.96 (t, J=7.2 Hz, 2H),2.47-2.54 (m, 4H), 1.686 (s, 4H), 1.47-1.45 (m, 3H), 1.31 (s, 3H), 0.98(d, J=7.2 Hz, 6H).

Embodiment 73 Ethyl1′-((1-(3-fluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate

Step 1 Ethyl1′-((1-(3-fluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate

Ethyl2′-oxo-1′-((4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate73a (0.30 g, 0.79 mmol) was dissolved in 5 mL DMSO,1-bromo-4-fluorobutane (0.15 g, 0.95 mmol), cesium carbonate (0.51 g,1.58 mmol), potassium iodide (0.01 g, 0.08 mmol) were added, stirringfor 5 h at 80° C. The reaction solution was cooled to r.t., 30 mL H₂Owas added, extracted with EA (20 mL×3), organic phases were combined andwashed in sequence with water (20 mL×2), saturated sodium chloridesolution (20 mL×2), dried over anhydrous sodium sulfate, filtered, thefiltrate was concentrated under reduced pressure, preparative HPLC wasused to purify and ethyl1′-((1-(3-fluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate73 (77 mg, white solid) was given, yield: 21.5%.

MS m/z (ESI): 455.3 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 7.64 (d, J=6.8 Hz, 1H), 7.20 (s, 1H), 7.17 (d,J=6.8 Hz, 1H), 7.06 (d, J=8.0 Hz, 1H), 5.00 (s, 2H), 4.52-4.35 (m, 4H),4.20 (d, J=6.8 Hz, 4H), 4.00 (s, 2H), 2.55-2.49 (m, 4H), 1.81-1.61 (m,8H), 1.31 (t, J=7.2 Hz, 3H).

Embodiment 74 Ethyl1′-((1-(3-cyanopropyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate

Step 1 Ethyl1′-((1-(3-cyanopropyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate

Ethyl2′-oxo-1′-((4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate74a (0.30 g, 0.79 mmol) was dissolved in 5 mL DMSO, 4-bromobutyronitrile(0.14 g, 0.95 mmol), cesium carbonate (0.51 g, 1.58 mmol), potassiumiodide (0.01 g, 0.08 mmol) were added, stirring for 5 h at 80° C. Thereaction solution was cooled to r.t., 30 mL H₂O was added, extractedwith EA (20 mL×3), organic phases were combined and washed in sequencewith water (20 mL×2), saturated sodium chloride solution (20 mL×2),dried over anhydrous sodium sulfate, filtered, the filtrate wasconcentrated under reduced pressure, preparative HPLC was used to purifyand ethyl1′-((1-(3-cyanopropyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate74 (77 mg, white solid) was given, yield: 21.8%.

MS m/z (ESI): 448.3 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 7.64 (d, J=7.8 Hz, 1H), 7.30 (t, J=7.2 Hz,1H), 7.20 (t, J=7.2 Hz, 1H), 7.07 (d, J=7.2 Hz, 1H), 5.02 (s, 2H), 4.30(s, 2H), 4.20 (d, J=7.2 Hz, 4H), 4.09 (t, J=7.6 Hz, 2H), 2.58-2.41 (m,6H), 2.01 (d, J=8 Hz, 2H), 1.82 (t, J=6 Hz, 4H), 1.31 (t, J=7.2 Hz, 3H).

Embodiment 75 Ethyl2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate

Step 1 Ethyl2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate

Ethyl2′-oxo-1′-((4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate75a (0.30 g, 0.79 mmol) was dissolved in 5 mL DMSO,4-bromo-1,1,1-trifluorobutytane (0.15 g, 0.95 mmol), cesium carbonate(0.51 g, 1.58 mmol), potassium iodide (0.01 g, 0.08 mmol) were added,stirring for 5 h at 80° C. The reaction solution was cooled to r.t., 30mL H₂O was added, extracted with EA (20 mL×3), organic phases werecombined and washed in sequence with water (20 mL×2), saturated sodiumchloride solution (20 mL×2), dried over anhydrous sodium sulfate,filtered, the filtrate was concentrated under reduced pressure,preparative HPLC was used to purify and ethyl2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate75 (57 mg, white solid) was given, yield: 14.6%.

MS m/z (ESI): 491.3 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 7.64 (d, J=7.6 Hz, 1H), 7.20 (d, J=7.2 Hz,1H), 7.17 (s, 1H), 7.09 (d, J=7.6 Hz, 1H), 5.01 (s, 2H), 4.36-4.06 (m,8H), 2.55-2.35 (m, 6H), 1.84 (d, J=7.6 Hz, 6H), 1.31 (s, 3H).

Embodiment 76 Ethyl1′-((1-(3-(methylsulfonyl)propyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate

Step 1 3-(Methyl sulfonyl)propan-1-ol

3-(Methylthio)propan-1-ol 76a (6.50 g, 61.21 mmol) was dissolved in 100mL DCM, benzoyl hydroperoxide (10.56 g, 61.21 mmol) was added at 0° C.,stirring for 5.5 h at r.t. The reaction solution was filtered, thefiltrate was concentrated under reduced pressure to obtain the crudeproduct of 3-(methylsulfonyl)propan-1-ol 76b (8.8 g, light yellow oil).

Step 2 1-Bromo-3-(methylsulfonyl)propane

3-(Methylsulfonyl)propan-1-ol 76b (1.50 g, 10.85 mmol) was dissolved in20 mL DCM, phosphorus tribromide (4.41 g, 16.28 mmol) was added at 0°C., stirring for 16 h at r.t. 100 mL saturated sodium carbonate aqueoussolution was added at 0° C., the mixture was extracted with DCM (100mL×3), organic phases were combined and washed in sequence with water(100 mL×2), saturated sodium chloride solution (100 mL×2), dried overanhydrous sodium sulfate, filtered, the filtrate was concentrated underreduced pressure to obtain 1-bromo-3-(methylsulfonyl)propane 76c (1.2 g,yellow oil).

1H NMR (400 MHz, CDCl₃) δ 3.57 (t, J=6.3 Hz, 2H), 3.29-3.18 (m, J=7.8Hz, 2H), 2.97 (s, 3H), 2.52-2.34 (m, J=6.8 Hz, 2H).

Step 3 Ethyl1′-((1-(3-(methylsulfonyl)propyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate

Ethyl2′-oxo-1′-((4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate(0.30 g, 0.79 mmol) was dissolved in 10 mL DMSO, the crude product of1-bromo-3-(methylsulphonyl)-propane 76c (0.19 g, 0.95 mmol), cesiumcarbonate (0.25 g, 0.79 mmol) were added, stirring for 1 h at r.t. Thereaction solution was cooled to r.t., 30 mL H₂O was added, extractedwith EA (20 mL×3), organic phases were combined and washed in sequencewith water (20 mL×2), saturated sodium chloride solution (20 mL×2),dried over anhydrous sodium sulfate, filtered, the filtrate wasconcentrated under reduced pressure, preparative HPLC was used to purifyand the target product ethyl 1′-((1-(3-(methylsulfonyl)propyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate76 (0.19 g, white solid) was given, yield: 48.6%.

MS m/z (ESI): 501.0 [M+1]

¹H NMR (400 MHz, CDCl₃) δ 7.58-7.45 (m, 1H), 7.37-7.29 (m, 1H),7.19-7.11 (m, J=7.5 Hz, 1H), 4.95 (br. s., 2H), 4.37 (d, J=8.2 Hz, 2H),4.26-4.04 (m, J=7.1 Hz, 7H), 3.09 (t, J=7.3 Hz, 2H), 2.94 (s, 3H),2.60-2.42 (m, 4H), 2.11 (br. s., 2H), 1.78 (br. s., 4H), 1.34-1.25 (m,3H).

Embodiment 77 Cyclopentyl1′-((1-(3-hydroxybutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate

Step 1 Cyclopentyl 2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate

Spiro[azetidine-3,3′-indoline]-2′-one hydrochloride 77a (9.82 g, 46.59mmol) was dissolved in 50 mL THF, NaOH (1.86 g, 46.59 mmol) aqueoussolution, sodium carbonate (4.94 g, 46.59 mmol) aqueous solution wereadded at 0° C., stirring for 10 min at 0° C., cyclopentylchlorocarbonate (9.00 g, 60.57 mmol) was added, stirring for 2 h at r.t.150 mL H₂O was added, extracted with EA (100 mL×3), organic phases werecombined and washed in sequence with water (100 mL×2), saturated sodiumchloride solution (100 mL×2), dried over anhydrous sodium sulfate,filtered, the filtrate was concentrated under reduced pressure, theresidue was purified by silica gel column chromatography with elutingsystem C to obtain cyclopentyl2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate 77b (1.54 g, yellowsolid), yield: 11.1%.

¹H NMR (400 MHz, CDCl₃) δ 9.17-9.10 (m, 1H), 7.52 (d, J=7.53 Hz, 1H),7.27 (s, 1H), 7.15-7.09 (m, 1H), 6.95 (d, J=7.53 Hz, 1H), 5.18-5.12 (m,1H), 4.40 (d, J=8.53 Hz, 2H), 1.86 (m, 2H), 1.72 (m, 4H), 1.64-1.52 (m,2H).

Step 2 Cyclopentyl1′-(2,2-diethoxyethyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate

Cyclopentyl 2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate 77b (1.54g, 5.38 mmol) was dissolved in 15 mL DMF, cesium carbonate (3.50 g,10.76 mmol), potassium carbonate (44.64 mg, 0.27 mmol) were added,stirring for 3 h at 90° C. 50 mL H₂O was added, the mixture wasextracted with EA (50 mL×3), organic phases were combined and washed insequence with water (50 mL×2), saturated sodium chloride solution (50mL×2), dried over anhydrous sodium sulfate, filtered, the filtrate wasconcentrated under reduced pressure, the residue was purified by silicagel column chromatography with eluting system C to give cyclopentyl1′-(2,2-diethoxyethyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate77c (1.60 g, light yellow oil), yield: 68.0%.

¹H NMR (400 MHz, CDCl₃) δ 7.53 (d, J=7.53 Hz, 1H), 7.35-7.26 (m, 1H),7.14 (t, J=7.53 Hz, 1H), 7.05 (d, J=7.78 Hz, 1H), 5.16 (t, J=5.77 Hz,1H), 4.71 (t, J=5.27 Hz, 1H), 4.40 (d, J=8.28 Hz, 2H), 4.18-4.06 (m,2H), 3.84 (d, J=5.27 Hz, 2H), 3.75 (dd, J=7.15, 9.16 Hz, 2H), 3.57-3.46(m, 2H), 1.95-1.82 (m, 2H), 1.80-1.69 (m, 4H), 1.60 (d, J=1.76 Hz, 2H),1.15 (t, J=6.90 Hz, 6H).

Step 3 Cyclopentyl2′-oxo-1′-(2-oxoethyl)spiro[azetidine-3,3′-indoline]-1-carboxylate

Cyclopentyl1′-(2,2-diethoxy)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate 77c(1.60 g, 3.98 mmol) was dissolved in 28 mL DCM and 5 mL H₂O, 28 mLtrifluoroacetic acid was added dropwise at 0° C., stirring for 2 h atr.t. 50 mL H₂O was added, the mixture was extracted with DCM (50 mL×3),organic phases were combined and washed in sequence with saturatedsodium bicarbonate aqueous solution (50 mL×2), saturated sodium chloridesolution (50 mL×2), dried over anhydrous sodium sulfate, filtered, thefiltrate was concentrated under reduced pressure to obtain the crudeproduct of cyclopentyl2′-oxo-1′-(2-oxoethyl)spiro[azetidine-3,3′-indoline]-1-carboxylate 77d(1.2 g, light yellow oil).

Step 4 Cyclopentyl2′-oxo-1′-((4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate

Cyclopentyl2′-oxo-1′-(2-oxoethyl)spiro[azetidine-3,3′-indoline]-1-carboxylate 77d(0.79 g, 2.41 mmol) was dissolved in 8 mL ethanol, 1,2-cyclohexanedione(0.32 g, 2.89 mmol), ammonium acetate (0.93 g, 12.05 mmol) were added,stirring at reflux for 6 h. The reaction solution was concentrated underreduced pressure, 30 mL H₂O was added, extracted with DCM (30 mL×3),organic phases were combined and washed in sequence with saturatedsodium bicarbonate aqueous solution (30 mL×2), saturated sodium chloridesolution (30 mL×2), dried over anhydrous sodium sulfate, filtered, thefiltrate was concentrated under reduced pressure, the residue waspurified by silica gel column chromatography with eluting system C toobtain cyclopentyl2′-oxo-1′-((4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate77e (0.78 g, yellow solid), yield: 70.8%.

¹H NMR (400 MHz, CDCl₃) δ 7.52 (d, J=7.53 Hz, 1H), 7.32 (s, 1H),7.25-7.19 (m, 1H), 7.14 (s, 1H), 5.16 (br. s., 1H), 4.89 (s, 2H), 4.37(d, J=8.03 Hz, 2H), 4.08 (d, J=9.03 Hz, 2H), 2.50 (br. s., 4H), 2.05 (s,2H), 1.94-1.82 (m, 2H), 1.80-1.67 (m, 6H), 1.65-1.55 (m, 2H).

Step 5 Cyclopentyl1′-((1-(3-hydroxybutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate

Cyclopentyl2′-oxo-1′-((4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate77e (0.17 g, 0.40 mmol) was dissolved in 5 mL DMSO, 4-bromobutyl acetate(0.09 g, 0.49 mmol), potassium carbonate (0.17 g, 1.21 mmol), potassiumiodide (6.71 mg, 0.04 mmol) were added, stirring for 5 h at 90° C. Thereaction solution was cooled to r.t., 30 mL H₂O was added, extractedwith EA (20 mL×3), organic phases were combined and washed in sequencewith water (20 mL×2), saturated sodium chloride solution (20 mL×2),dried over anhydrous sodium sulfate, filtered, the filtrate wasconcentrated under reduced pressure to obtain white solid. 3 mL 1M NaOHaqueous solution was added to dissolve, stirring for 1 h at r.t. 30 mLwater was added into the reaction solution, the mixture was extractedwith EA (30 mL×2), organic phase was combined and washed with saturatedsodium chloride solution (20 mL×2), dried over anhydrous sodium sulfate,filtered, the filtrate was concentrated under reduced pressure,preparative HPLC was used to purify and the target product cyclopentyl1′-((1-(3-hydroxybutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate77 (11 mg, white solid) was given, yield: 16.9%.

MS m/z (ESI): 493.4 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 1.65-1.80 (m, 15H) 2.47-2.54 (m, 4H) 3.57 (t,J=7.2 Hz, 2H) 3.96 (t, J=6.8 Hz, 2H) 4.21 (d, J=6.8 Hz, 4H) 4.30 (t,J=7.6 Hz, 2H) 5.01 (s, 2H) 7.06 (t, J=8.0 Hz, 1H) 7.19 (d, J=7.2 Hz, 1H)7.28 (t, J=7.6 Hz, 1H) 7.63 (d, J=7.2 Hz, 1H).

Embodiment 78 Isopropyl5′-bromo-1′-((1-(4-hydroxybutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate

Step 1 Isopropyl5′-bromo-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate

Isopropyl 2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate 78a (1.00g, 3.84 mmol) was dissolved in 10 mL ethanol, N-bromosuccinimide (0.62g, 4.61 mmol), 2,2′-azobis(2-methylpropionitrile) (0.06 g, 0.38 mmol)were added, stirring for 2 h at 80° C. The reaction solution wasconcentrated under reduced pressure, 50 mL H₂O was added, extracted withEA (50 mL×3), organic phases were combined and washed in sequence withwater (50 mL×2), saturated sodium chloride solution (50 mL×2), driedover anhydrous sodium sulfate, filtered, the filtrate was concentratedunder reduced pressure, the residue was purified by silica gel columnchromatography with eluting system C to obtain isopropyl5′-bromo-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate 78b (0.90 g,yellow solid), yield: 95.0%.

¹H NMR (400 MHz, CD₃OD) δ 7.86-7.69 (m, 1H), 7.53-7.35 (m, 1H),7.02-6.72 (m, 1H), 5.10-4.89 (m, 1H), 4.38-4.24 (m, 2H), 4.20-4.00 (m,2H), 1.30 (d, J=6.27 Hz, 6H).

Step 2 Isopropyl5′-bromo-1′-(2,2-diethoxy)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate

Isopropyl 5′-bromo-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate78b (0.8 g, 2.46 mmol) was dissolved in 10 mL DMF,2-bromo-1,1-diethoxyethane (0.53 g, 2.71 mmol), cesium carbonate (1.6 g,4.92 mmol) were added, stirring for 5 h at 90° C. The reaction solutionwas cooled to r.t., 100 mL H₂O was added, extracted with EA (100 mL×3),organic phases were combined and washed in sequence with water (100mL×2), saturated sodium chloride solution (100 mL×2), dried overanhydrous sodium sulfate, filtered, the filtrate was concentrated underreduced pressure to obtain isopropyl5′-bromo-1′-(2,2-diethoxy)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate78c (0.70 g, yellow oil), yield: 64.0%.

¹H NMR (400 MHz, CD₃OD) δ 7.86-7.69 (m, 1H), 7.53-7.35 (m, 1H),7.02-6.72 (m, 1H), 5.10-4.89 (m, 2H), 4.38-4.24 (m, 2H), 4.20-4.00 (m,2H), 3.80-3.50 (m, 6H), 1.30 (d, J=6.27 Hz, 6H), 1.20-1.10 (m, 6H).

Step 3 Isopropyl5′-bromo-2′-oxo-1′-(2-oxoethyl)spiro[azetidine-3,3′-indoline]-1-carboxylate

Isopropyl5′-bromo-1′-(2,2-diethoxy)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate78c (0.5 g, 1.13 mmol) was dissolved in 45 mL DCM and 10 mL H₂O, 45 mLtrifluoroacetic acid was added, stirring for 2 h at r.t. Sodiumcarbonate was added to adjust pH to 9, 100 mL H₂O was added, the mixturewas extracted with DCM (100 mL 3), organic phases were combined andwashed in sequence with water (100 mL×2), saturated sodium chloridesolution (100 mL×2), dried over anhydrous sodium sulfate, filtered, thefiltrate was concentrated under reduced pressure to obtain the crudeproduct of isopropyl5′-bromo-2′-oxo-1′-(2-oxoethyl)spiro[azetidine-3,3′-indoline]-1-carboxylate78d (0.40 g, yellow oil), yield: 94.0%.

Step 4 Isopropyl5′-bromo-2′-oxo-1′-((4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate

Isopropyl5′-bromo-2′-oxo-1′-(2-oxoethyl)spiro[azetidine-3,3′-indoline]-1-carboxylate78d (0.4 g, 1.05 mmol) was dissolved in 5 mL ethanol,1,2-cyclohexanedione (0.14 g, 1.26 mmol), ammonium acetate (0.40 g, 5.25mmol) were added, refluxing for 4 h. The reaction solution was cooled tor.t., 100 mL H₂O was added, extracted with EA (100 mL×3), organic phaseswere combined and washed in sequence with water (100 mL×2), saturatedsodium chloride solution (100 mL×2), dried over anhydrous sodiumsulfate, filtered, the filtrate was concentrated under reduced pressure,the residue was purified by silica gel column chromatography witheluting system C to obtain isopropyl5′-bromo-2′-oxo-1′-((4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate78e (0.30 g, yellow solid), yield: 60.0%.

¹H NMR (400 MHz, CDCl₃) δ 7.86-7.69 (m, 1H), 7.53-7.35 (m, 1H),7.02-6.72 (m, 1H), 5.30 (s, 1H), 5.10-4.89 (m, 3H), 4.38-4.24 (m, 2H),4.20-4.00 (m, 2H), 2.60-2.50 (m, 4H), 1.70-1.60 (m, 4H), 1.30 (d, J=6.27Hz, 6H).

Step 5 Isopropyl5′-bromo-1′-((1-(4-hydroxybutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate

Isopropyl5′-bromo-2′-oxo-1′-((4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate78e (0.14 g, 0.30 mmol) was dissolved in 5 mL DMSO, 4-bromobutyl acetate(0.07 g, 0.38 mmol), potassium carbonate (0.12 g, 0.89 mmol), potassiumiodide (4.9 mg, 0.03 mmol) were added, stirring for 16 h at 90° C. Thereaction solution was cooled to r.t., 30 mL H₂O was added, extractedwith EA (20 mL×3), organic phases were combined and washed in sequencewith water (20 mL×2), saturated sodium chloride solution (20 mL×2),dried over anhydrous sodium sulfate, filtered, the filtrate wasconcentrated under reduced pressure to obtain yellow solid. 3 mL 1M NaOHaqueous solution was added to dissolve, stirring for 1 h at r.t. 30 mLwater was added into the reaction solution, the mixture was extractedwith EA (30 mL×2), organic phases were combined and washed withsaturated sodium chloride solution (20 mL×2), dried over anhydroussodium sulfate, filtered, the filtrate was concentrated under reducedpressure, preparative HPLC was used to purify and the target productisopropyl5′-bromo-1′-((1-(4-hydroxybutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate78 (9 mg, white solid), yield: 5.7%.

MS m/z (ESI): 546.3 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 7.88-7.79 (m, 1H), 7.54-7.38 (m, 1H),6.98-6.91 (m, 1H), 5.00 (s, 2H), 4.80-4.70 (m, 1H), 4.47-4.29 (m, 2H),4.28-4.09 (m, 2H), 4.07-3.87 (m, 2H), 3.59 (s, 2H), 2.70-2.38 (m, 4H),1.93-1.47 (m, 8H), 1.31 (d, J=6.27 Hz, 6H).

Embodiment 79 Isopropyl5′-bromo-2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate

Step 1 Ethyl1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazole-2-carboxylate

Ethyl 4,5,6,7-tetrahydro-1H-benzo[d]imidazole-2-carboxylate 79a (2.0 g,10.3 mmol) was dissolved in 35 mL DMF, 4-bromo-1,1,1-trifluorobutane(2.16 g, 11.33 mmol), cesium carbonate (6.7 g, 20.6 mmol) were added,stirring for 18 h at 90° C., the reaction mixture was cooled to r.t.,150 mL H₂O was added, extracted with EA (100 mL 3), organic phases werecombined and washed in sequence with water (100 mL×2), saturated sodiumchloride solution (100 mL×2), dried over anhydrous sodium sulfate,filtered, the filtrate was concentrated under reduced pressure, theresidue was purified by silica gel column chromatography with elutingsystem C to obtain ethyl1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazole-2-carboxylate79b (3.1 g, yellow oil), yield: 91.0%.

¹H NMR (400 MHz, CDCl₃) δ 4.43-4.27 (m, 4H), 2.64 (t, J=5.8 Hz, 2H),2.54 (t, J=6.0 Hz, 2H), 2.22-2.07 (m, 2H), 2.03-1.94 (m, 2H), 1.88-1.79(m, 4H), 1.40 (t, J=7.3 Hz, 3H).

Step 2 (1-(4,4,4-Trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methanol

Ethyl1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazole-2-carboxylate79c (3.2 g, 10.52 mmol) was dissolved in 3 mL ethanol, cerous chloride(2.59 g, 10.52 mmol), sodium borohydride (0.40 g, 10.52 mmol) wereadded, stirring for 8 h at r.t. 200 mL H₂O was added at 0° C., themixture was extracted with EA (150 mL×3), organic phases were combinedand washed in sequence with water (150 mL×2), saturated sodium chloridesolution (150 mL×2), dried over anhydrous sodium sulfate, filtered, thefiltrate was concentrated under reduced pressure, the residue waspurified by silica gel column chromatography with eluting system A toobtain(1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methanol79c (2.2 g, white solid), yield: 78.1%.

¹H NMR (400 MHz, CDCl₃) δ 4.61 (s, 2H), 3.98 (t, J=7.4 Hz, 2H), 2.51(td, J=5.9, 11.1 Hz, 4H), 2.25-2.09 (m, J=9.0 Hz, 2H), 2.09-1.96 (m,J=7.3 Hz, 2H), 1.90-1.74 (m, J=5.3 Hz, 4H).

Step 3 Isopropyl5′-bromo-2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate

Isopropyl 5′-bromo-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate(70.00 mg, 0.27 mmol) was dissolved in 3 mL THF,(1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methanol79c (0.11 g, 0.32 mmol), triphenylphosphine (0.08 g, 0.32 mmol) wereadded, diisopropyl azodicarboxylate (64.7 mg, 0.32 mmol) was addeddropwise at 0° C., stirring for 16 h at r.t. 30 mL H₂O was added, themixture was extracted with EA (20 mL×3), organic phases were combinedand washed in sequence with water (20 mL×2), saturated sodium chloridesolution (20 mL×2), dried over anhydrous sodium sulfate, filtered, thefiltrate was concentrated under reduced pressure, preparative HPLC wasused to purify and the target product isopropyl5′-bromo-2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate79 (11 mg, white solid), yield: 11.5%.

MS m/z (ESI): 583.1 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 7.84-7.80 (m, 1H), 7.48-7.43 (m, 1H),7.03-6.99 (m, 1H), 4.99 (s, 2H), 4.39-4.30 (m, 2H), 4.23-4.14 (m, 2H),4.11-4.02 (m, 2H), 2.60-2.44 (m, 5H), 2.34-2.23 (m, 2H), 1.95-1.75 (m,6H), 1.31 (d, J=6.02 Hz, 6H).

Embodiment 80 Isopropyl5′-chloro-2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate

Step 1 Isopropyl5′-chloro-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate

Isopropyl 2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate 80a (2.00g, 7.68 mmol) was dissolved in 15 mL ethanol, N-chlorosuccinimide (1.23g, 9.22 mmol), AIBN (0.13 g, 0.77 mmol) were added, stirring for 3 h at80′C. The reaction solution was concentrated under reduced pressure, 50mL H₂O was added, extracted with EA (100 mL×3), organic phases werecombined and washed in sequence with water (50 mL×2), saturated sodiumchloride solution (50 mL×2), dried over anhydrous sodium sulfate,filtered, the filtrate was concentrated under reduced pressure, theresidue was purified by silica gel column chromatography with elutingsystem C to obtain isopropyl5′-chloro-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate 80b (2.01g, yellow solid), yield: 62.2%.

Step 2 Isopropyl5′-chloro-2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate

Isopropyl 5′-bromo-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate80b (67.0 mg, 0.23 mmol) was dissolved in 2 mL THF,(1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methanol(50 mg, 0.19 mmol), triphenylphosphine (60 mg, 0.23 mmol) were added,diisopropyl azodicarboxylate (46.26 mg, 0.23 mmol) was added dropwise at0° C., stirring for 4 h at r.t. 30 mL H₂O was added, the mixture wasextracted with EA (20 mL×3), organic phases were combined and washed insequence with water (20 mL×2), saturated sodium chloride solution (20mL×2), dried over anhydrous sodium sulfate, filtered, the filtrate wasconcentrated under reduced pressure, preparative HPLC was used to purifyand the target product isopropyl5′-chloro-2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate80 (10 mg, white solid) was given, yield: 18.2%.

MS m/z (ESI): 539.2 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 7.70 (d, J=1.5 Hz, 1H), 7.31 (dd, J=1.8, 8.3Hz, 1H), 7.06 (d, J=8.5 Hz, 1H), 5.00 (s, 2H), 4.34 (d, J=8.5 Hz, 2H),4.18 (d, J=8.5 Hz, 2H), 4.08 (d, J=7.5 Hz, 1H), 2.63-2.42 (m, 4H), 2.29(dd, J=10.8, 16.3 Hz, 2H), 2.18 (s, 1H), 2.02-1.67 (m, 6H), 1.31 (d,J=6.5 Hz, 6H).

Embodiment 81 Isopropyl6′-chloro-2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate

Step 1 tert-Butyl3-((2-bromo-5-chlorophenyl)carbamoyl)azetidine-1-carboxylate

2-Bromo-5-chloroaniline 81a (4.13 g, 20.0 mmol) was dissolved in 50 mLEA, 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (4.83 g, 24.0mmol), TEA (4.05 g, 40.00 mmol) were added, tripropyl phosphoricanhydride (74.35 g, 116.84 mmol) was added dropwise at 0° C., stirringfor 16 h at r.t. 50 mL H₂O was added, extracted with EA (50 mL×3),organic phases were combined and washed in sequence with water (50mL×2), saturated sodium chloride solution (50 mL×2), dried overanhydrous sodium sulfate, filtered, the filtrate was concentrated underreduced pressure to obtain tert-butyl3-((2-bromo-5-chlorophenyl)carbamoyl)azetidine-1-carboxylate 81b (7.3 g,light yellow solid), yield: 84.3%.

¹H NMR (400 MHz, CDCl₃) δ 8.50 (br. s., 1H), 7.66 (br. s., 1H), 7.49 (d,J=8.53 Hz, 1H), 7.03 (dd, J=2.26, 8.53 Hz, 1H), 4.26-4.16 (m, 4H), 3.42(s, 1H), 1.48 (s, 9H).

Step 2 tert-Butyl3-((2-bromo-5-chlorophenyl)(4-methoxybenzyl)carbamoyl)azetidine-1-carboxylate

tert-Butyl 3-((2-bromo-5-chlorophenyl)carbamoyl)azetidine-1-carboxylate81b (7.30 g, 18.7 mmol) was dissolved in 100 mL DMF, cesium carbonate(9.16 g, 28.1 mmol) was added, 4-methoxybenzyl chloride (3.52 g, 22.48mmol) was added dropwise, stirring for 16 h at 90° C. The reactionsolution was cooled to r.t., 200 mL H₂O was added, extracted with EA(200 mL×3), organic phases were combined and washed in sequence withwater (200 mL×2), saturated sodium chloride solution (200 mL×2), driedover anhydrous sodium sulfate, filtered, the filtrate was concentratedunder reduced pressure to obtain tert-butyl3-((2-bromo-5-chlorophenyl)(4-methoxybenzyl)carbamoyl)azetidine-1-carboxylate81c (7.3 g, light yellow oil), yield: 72.9%.

¹H NMR (400 MHz, CDCl₃) δ 7.60 (d, J=8.53 Hz, 1H), 7.21 (dd, J=2.51,8.53 Hz, 1H), 7.09 (d, J=8.53 Hz, 2H), 6.81 (d, J=8.53 Hz, 2H), 6.67 (d,J=2.26 Hz, 1H), 5.47 (d, J=14.31 Hz, 1H), 4.31-4.20 (m, 1H), 4.04 (d,J=14.30 Hz, 2H), 3.79 (s, 3H), 3.76-3.69 (m, 1H), 3.68-3.59 (m, 1H),3.04 (s, 1H), 1.41 (s, 9H).

Step 3 tert-Butyl6′-chloro-1′-(4-methoxybenzyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate

tert-Butyl3-((2-bromo-5-chlorophenyl)(4-methoxybenzyl)carbamoyl)azetidine-1-carboxylate81c (7.30 g, 14.4 mmol) was dissolved in 100 mL 1,4-dioxane, palladiumdiacetate (0.16 g, 0.72 mmol), sodium tert-butoxide (2.07 g, 21.57 mmol)and tricyclohexylphosphine (2.02 g, 1.44 mmol) were added, stirring for16 h at 120° C. The reaction solution was concentrated under reducedpressure, cooled to r.t., 200 mL H₂O was added, extracted with EA (200mL×3), organic phases were combined and washed in sequence with water(200 mL×2), saturated sodium chloride solution (200 mL×2), dried overanhydrous sodium sulfate, filtered, the filtrate was concentrated underreduced pressure, the residue was purified by silica gel columnchromatography with eluting system C to obtain tert-butyl6′-chloro-1′-(4-methoxybenzyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate81d (3.6 g, light yellow oil), yield: 52.5%.

¹H NMR (400 MHz, CDCl₃) δ 7.45 (d, J=8.03 Hz, 1H), 7.22 (d, J=8.53 Hz,2H), 7.08 (dd, J=1.76, 7.78 Hz, 1H), 6.86 (d, J=8.53 Hz, 2H), 6.75 (d,J=1.51 Hz, 1H), 4.80 (s, 2H), 4.41 (d, J=8.53 Hz, 2H), 4.05 (d, J=8.53Hz, 2H), 3.81-3.77 (m, 3H), 1.49 (s, 9H).

Step 4 Isopropyl6′-chloro-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate

tert-Butyl6′-chloro-1′-(4-methoxybenzyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate81d (0.80 g, 1.49 mmol) was dissolved in 10 mL trifluoroacetic acid,trifluoromethanesulfonic acid (0.67 g, 4.48 mmol) was added dropwise at0° C., stirring for 16 h at r.t. The reaction solution was concentratedunder reduced pressure, 20 mL THF, 10 mL H₂O were added into theresidue, sodium carbonate was added to adjust pH to 9˜10, isopropylchloroformate (0.22 g, 1.79 mmol) was added dropwise at 0° C., stirringfor 2 h at r.t. 100 mL H₂O was added, the mixture was extracted with EA(100 mL×3), organic phases were combined and washed in sequence withwater (100 mL×2), saturated sodium chloride solution (100 mL×2), driedover anhydrous sodium sulfate, filtered, the filtrate was concentratedunder reduced pressure, the residue was purified by silica gel columnchromatography with eluting system C to obtain isopropyl6′-chloro-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate 81e (0.23g, black oil), yield: 52.4%.

¹H NMR (400 MHz, CDCl₃) δ 8.85 (br. s., 1H), 7.45 (d, J=8.03 Hz, 1H),7.11 (dd, J=2.01, 8.03 Hz, 1H), 6.96 (d, J=1.51 Hz, 1H), 4.97 (td,J=6.09, 12.42 Hz, 1H), 4.41 (d, J=8.53 Hz, 2H), 4.09 (d, J=8.03 Hz, 2H),1.28 (d, J=6.53 Hz, 6H).

Step 5 Isopropyl6′-chloro-2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate

Isopropyl 6′-chloro-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate81e (70.8 mg, 0.24 mmol) was dissolved in 2 mL THF,(1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methanol(70 mg, 0.27 mmol), triphenylphosphine (84 mg, 0.32 mmol) were added,diisopropyl azodicarboxylate (64.7 mg, 0.32 mmol) was added dropwise at0° C., stirring for 6 h at r.t. 30 mL H₂O was added, the mixture wasextracted with EA (20 mL×3), organic phases were combined and washed insequence with water (20 mL×2), saturated sodium chloride solution (20mL×2), dried over anhydrous sodium sulfate, filtered, the filtrate wasconcentrated under reduced pressure, preparative HPLC was used to purifyand the target product isopropyl6′-chloro-2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate81 (17.5 mg, white solid) was given, yield: 12.0%.

MS m/z (ESI): 339.3 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 7.62 (d, J=7.8 Hz, 1H), 7.23-7.12 (m, J=1.8Hz, 2H), 4.99 (s, 3H), 4.34 (d, J=8.5 Hz, 2H), 4.16 (d, J=8.5 Hz, 2H),4.07 (t, J=7.9 Hz, 2H), 2.64-2.44 (m, 4H), 2.37-2.19 (m, J=5.5 Hz, 2H),1.96-1.75 (m, 6H), 1.30 (d, J=6.0 Hz, 6H).

Embodiment 82 Isopropyl6′-fluoro-2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate

Step 1 tert-Butyl3-((2-bromo-5-fluorophenyl)carbamoyl)azetidine-1-carboxylate

2-Bromo-5-fluoroaniline 82a (18.50 g, 97.36 mmol) was dissolved in 200mL EA, 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (23.51 g, 0.12mmol), TEA (19.70 g, 194.73 mmol) were added, tripropyl phosphoricanhydride (74.35 g, 116.84 mmol) was added portionwise at 0° C.,stirring for 16 h at r.t. 500 mL H₂O was added, the mixture wasextracted with EA (500 mL×3), organic phases were combined and washed insequence with water (500 mL×2), saturated sodium chloride solution (500mL×2), dried over anhydrous sodium sulfate, filtered, the filtrate wasconcentrated under reduced pressure, the residue was purified by silicagel column chromatography with eluting system C to obtain tert-butyl3-((2-bromo-5-fluorophenyl)carbamoyl)azetidine-1-carboxylate 82b (26.5g, white solid), yield: 65.6%.

¹H NMR (400 MHz, CDCl₃) δ 8.32-8.21 (m, 1H), 7.75-7.66 (m, 1H),7.55-7.45 (m, 1H), 6.80-6.71 (m, 1H), 4.28-4.08 (m, 4H), 3.40 (s, 1H),1.46 (s, 9H).

Step 2 tert-Butyl3-((2-bromo-5-fluorophenyl)(4-methoxybenzyl)carbamoyl)azetidine-1-carboxylate

tert-Butyl 3-((2-bromo-5-fluorophenyl)carbamoyl)azetidine-1-carboxylate82b (26.0 g, 69.66 mmol) was dissolved in 200 mL DMF, cesium carbonate(45.39 g, 0.14 mmol), 1-chloromethyl-4-methoxybenzene (16.36 g, 0.10mmol) were added, stirring for 16 h at 90° C. 200 mL H₂O was added, themixture was extracted with EA (300 mL×3), organic phases were combinedand washed in sequence with water (300 mL×2), saturated sodium chloridesolution (300 mL×2), dried over anhydrous sodium sulfate, filtered, thefiltrate was concentrated under reduced pressure, the residue waspurified by silica gel column chromatography with eluting system C toobtain tert-butyl3-((2-bromo-5-fluorophenyl)(4-methoxybenzyl)carbamoyl)azetidine-1-carboxylate82c (25.0 g, white solid), yield: 61.8%.

¹H NMR (400 MHz, CDCl₃) δ 7.72-7.62 (m, 1H), 7.11 (d, J=8.28 Hz, 2H),7.05-6.94 (m, 1H), 6.82 (d, J=8.28 Hz, 2H), 6.50-6.38 (m, 1H), 5.60-5.48(m, 1H), 4.36-4.24 (m, 1H), 4.03 (d, J=14.05 Hz, 2H), 3.81 (s, 3H),3.78-3.60 (m, 2H), 3.14-3.02 (m, 1H), 1.49-1.37 (m, 10H).

Step 3 tert-Butyl6′-fluoro-1′-(4-methoxybenzyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate

tert-Butyl3-((2-bromo-5-fluorophenyl)(4-methoxybenzyl)carbamoyl)azetidine-1-carboxylate82c (18.5 g, 37.5 mmol) was dissolved in 200 mL 1,4-dioxane, palladiumacetate (0.42 g, 1.88 mmol), sodium tert-butoxide (5.41 g, 56.25 mmol)and tricyclohexylphosphine (5.26 g, 3.75 mmol) were added, stirring for16 h at 120° C. The reaction solution was cooled to r.t., 200 mL H₂O wasadded, extracted with EA (200 mL×3), organic phases were combined andwashed in sequence with water (200 mL×2), saturated sodium chloridesolution (200 mL×2), dried over anhydrous sodium sulfate, filtered, thefiltrate was concentrated under reduced pressure, the residue waspurified by silica gel column chromatography with eluting system C toobtain tert-butyl6′-fluoro-1′-(4-methoxybenzyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate82d (7.1 g, yellow oil), yield: 39.0%.

¹H NMR (400 MHz, CDCl₃) δ 7.727.62 (m, 1H), 7.11 (d, J=8.28 Hz, 2H),7.05-6.94 (m, 1H), 6.82 (d, J=8.28 Hz, 2H), 6.50-6.38 (m, 1H), 5.60-5.48(m, 1H), 4.36-4.24 (m, 1H), 4.03 (d, J=14.05 Hz, 2H), 3.81 (s, 3H),3.78-3.60 (m, 2H), 1.49-1.37 (m, 9H).

Step 4 Isopropyl6′-fluoro-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate

tert-Butyl6′-fluoro-1′-(4-methoxybenzyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate82d (2.0 g, 4.85 mmol) was dissolved in 10 mL trifluoroacetic acid,trifluoromethanesulfonic acid (2.18 g, 14.55 mmol) was added dropwise at0° C., stirring for 16 h at r.t. The reaction solution was concentratedunder reduced pressure, 20 mL THF, 10 mL H₂O were added into theresidue, sodium carbonate was added to adjust pH to 9˜10, isopropylchloroformate (1.04 g, 8.49 mmol) was added dropwise at 0° C., stirringfor 4 h at r.t. 100 mL H₂O was added, the mixture was extracted with EA(100 mL×3), organic phases were combined and washed in sequence withwater (100 mL×2), saturated sodium chloride solution (100 mL×2), driedover anhydrous sodium sulfate, filtered, the filtrate was concentratedunder reduced pressure, the residue was purified by silica gel columnchromatography with eluting system C to obtain isopropyl6′-fluoro-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate 82e (0.97g, yellow solid), yield: 48.1%.

MS m/z (ESI): 278.9 [M+1]

Step 5 Isopropyl6′-fluoro-2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate

Isopropyl 6′-fluoro-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate82e (0.1 g, 0.38 mmol) was dissolved in 5 mL THF,(1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methanol(0.1 g, 0.38 mmol), triphenylphosphine (0.1 g, 0.38 mmol) were added,diisopropyl azodicarboxylate (92.5 mg, 0.46 mmol) was added dropwise at0° C., stirring for 16 h at r.t. 30 mL H₂O was added, the mixture wasextracted with EA (20 mL×3), organic phases were combined and washed insequence with water (20 mL×2), saturated sodium chloride solution (20mL×2), dried over anhydrous sodium sulfate, filtered, the filtrate wasconcentrated under reduced pressure, preparative HPLC was used to purifyand the target product isopropyl6′-fluoro-2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate82 (40 mg, white solid) was given, yield: 20.1%.

MS m/z (ESI): 523.4 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 7.67-7.60 (m, 1H), 7.05-6.81 (m, 2H), 4.99 (s,2H), 4.61 (s, 1H), 4.43-4.28 (m, 2H), 4.21-4.09 (m, 2H), 4.11-3.95 (m,2H), 2.64-2.43 (m, 3H), 2.40-2.13 (m, 3H), 1.85 (br. s., 6H), 1.30 (d,J=6.27 Hz, 6H).

Embodiment 83 Ethyl6′-fluoro-2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate

Step 1 tert-Butyl6′-fluoro-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate

tert-Butyl6′-fluoro-1′-(4-methoxybenzyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate83a (2.0 g, 4.85 mmol) was dissolved in 10 mL trifluoroacetic acid,trifluoromethanesulfonic acid (2.2 g, 14.55 mmol) was added dropwise at0° C., stirring for 16 h at r.t. The reaction solution was concentratedunder reduced pressure to give red oil. 20 mL THF, 20 mL H₂O were addedinto the residue, sodium carbonate was added to adjust pH to 9˜10,di-tert-butyl dicarbonate (1.38 g, 6.30 mmol) was added, stirring for 4h at r.t. 100 mL H₂O was added, the mixture was extracted with EA (100mL×3), organic phases were combined and washed in sequence with water(100 mL×2), saturated sodium chloride solution (100 mL×2), dried overanhydrous sodium sulfate, filtered, the filtrate was concentrated underreduced pressure, the residue was purified by silica gel columnchromatography with eluting system C to obtain tert-butyl6′-fluoro-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate 83b (1.1 g,white solid), yield: 27.0%.

Step 2 tert-Butyl6′-fluoro-2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate

tert-Butyl 6′-fluoro-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate83b (1.0 g, 3.42 mmol) was dissolved in 10 mL THF,(1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methanol(1.1 g, 4.12 mmol), diisopropyl azodicarboxylate (0.83 g, 4.10 mmol)were added, triphenylphosphine (1.1 g, 4.10 mmol) was added at 0° C.,stirring for 16 h at r.t. 30 mL H₂O was added, the mixture was extractedwith EA (20 mL×3), organic phases were combined and washed in sequencewith water (20 mL×2), saturated sodium chloride solution (20 mL×2),dried over anhydrous sodium sulfate, filtered, the filtrate wasconcentrated under reduced pressure, the residue was purified by silicagel column chromatography with eluting system C to obtain tert-butyl6′-fluoro-2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate83c (1.1 g, white solid), yield: 27.0%.

¹H NMR (400 MHz, CD₃Cl₃) δ 7.57 (d, J=1.00 Hz, 1H), 7.39-7.34 (m, 1H),6.85-6.78 (m, 1H), 4.95 (s, 2H), 4.31 (s, 2H), 4.17-4.09 (m, 1H), 4.03(s, 2H), 4.00-3.93 (m, 2H), 2.57 (br. s., 2H), 2.45 (br. s., 3H),2.24-2.08 (m, 6H), 1.49 (s, 9H).

Step 3 Ethyl6′-fluoro-2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate

tert-Butyl6′-fluoro-2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate83c (0.6 g, 0.52 mmol) was dissolved in 10 mL DCM, trifluoroacetic acid(4.0 g, 35.1 mmol) was added, stirring for 1 h at r.t. The reactionsolution was concentrated under reduced pressure, the residue wasdissolved in 5 mL DCM, TEA (0.3 g, 2.56 mmol), ethyl chloroformate (55mg, 0.51 mmol) were added in sequence at 0° C., stirring for 1 h at r.t.50 mL H₂O was added, the mixture was extracted with DCM (80 mL×3),organic phases were combined and washed in sequence with water (50 mL),saturated sodium chloride solution (50 mL), dried over anhydrous sodiumsulfate, filtered, the filtrate was concentrated under reduced pressure,preparative HPLC was used to purify and the target product ethyl6′-fluoro-2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate83 (47 mg, white solid) was given, yield: 18.0%.

MS m/z (ESI): 509.3 [M+1]

¹H NMR (400 MHz, MeOD) δ 7.67-7.62 (m, 1H), 6.97-6.83 (m, 2H), 4.99 (s,2H), 4.64-4.40 (m, 2H), 4.39-4.30 (m, 2H), 4.24-4.14 (m, 3H), 4.12-4.03(m, 2H), 2.60-2.47 (m, 4H), 2.34-2.22 (m, 2H), 1.92-1.78 (m, 5H), 1.31(s, 3H).

Embodiment 841-(Cyclopropanecarbonyl)-6′-fluoro-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one

Step 11-(Cyclopropanecarbonyl)-6′-fluoro-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one

6′-Fluoro-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one84a (0.3 g, 0.69 mmol) was dissolved in 5 mL DCM, cyclopropanecarboxylicacid (77 mg, 0.89 mmol),2-(7-aza-1H-benzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (0.52 g, 1.37 mmol) and N,N-diisopropylethylamine(0.18 g, 1.37 mmol) were added, stirring for 2 h at r.t. 50 mL H₂O wasadded, the reaction solution was extracted with DCM (80 mL×3), organicphases were combined and washed in sequence with water (50 mL),saturated sodium chloride solution (50 mL), dried over anhydrous sodiumsulfate, filtered, the filtrate was concentrated under reduced pressure,preparative HPLC was used to purify and the target product1-(cyclopropanecarbonyl)-6′-fluoro-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one84 (42 mg, white solid), yield: 12.1%.

MS m/z (ESI): 527.4 [M+23]

¹H NMR (400 MHz, CD₃OD) δ 7.69-7.64 (m, 1H), 6.97-6.87 (m, 2H), 5.01 (s,2H), 4.70-4.66 (m, 1H), 4.59-4.54 (m, 1H), 4.38-4.32 (m, 1H), 4.22-4.16(m, 1H), 4.12-4.05 (m, 2H), 2.61-2.48 (m, 4H), 2.35-2.23 (m, 2H),1.94-1.77 (m, 6H), 1.71-1.54 (m, 1H), 1.01-0.88 (m, 4H).

Embodiment 85 Isopropyl4′-chloro-1′-((1-(4-hydroxybutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate

Step 1 3-Chloro-2-iodobenzoic acid

2,2,6,6-Tetramethylpiperidine (39.7 g, 281.03 mmol) was dissolved in 100mL anhydrous THF, under nitrogen gas atmosphere n-BuLi (18.0 g, 281.03mmol) was slowly added dropwise at −78° C., stirring for 1 h at −78° C.3-Chlorobenzoic acid 85a (20.0 g, 127.7 mmol) in 150 mL THF was slowlyadded dropwise into the reaction solution, stirring for 4 h at −78° C.Iodine (129.7 g, 510.96 mmol) in 250 mL THF was slowly added dropwiseinto the reaction solution, stirring for 3 h at −78° C. The reaction wasquenched by H₂O, acidified with 4M HCl aqueous solution, extracted withEA, washed with sodium thiosulfate, organic phases were combined anddried over anhydrous sodium sulfate, filtered, the filtrate wasconcentrated under reduced pressure to obtain the crude product of3-chloro-2-iodobenzoic acid 85b (30 g, white solid).

¹H NMR (400 MHz, CD₃Cl₃) δ 7.72 (d, J=7.5 Hz, 1H) 7.65 (d, J=7.8 Hz, 1H)7.39 (t, J=7.9 Hz, 1H).

Step 2 tert-Butyl (3-chloro-2-iodophenyl)carbamate

3-Chloro-2-iodobenzoic acid 85b (30.0 g, 106.21 mmol) and diphenylazidophosphate (58.5 g, 212.42 mmol) were dissolved in 10 mLtert-butanol, TEA (21.5 g, 212.42 mmol) was added at r.t., stirring for12 h at 120° C. The reaction was quenched by H₂O, extracted with EA,washed with water and saturated sodium chloride aqueous solution,organic phases were combined and dried over anhydrous sodium sulfate,filtered, the filtrate was concentrated under reduced pressure, theresidue was purified by silica gel column chromatography with elutingsystem C to obtain tert-butyl (3-chloro-2-iodophenyl)carbamate 85c (34.0g, yellow oil), yield: 90.5%.

¹H NMR (400 MHz, CD₃Cl₃) δ 8.03-7.94 (m, 1H) 7.26 (t, J=8.2 Hz, 1H)7.20-7.14 (m, 1H) 7.08 (br. s., 1H) 1.56 (s, 9H).

Step 3 3-Chloro-2-iodoaniline hydrochloride

tert-Butyl (3-chloro-2-iodophenyl)carbamate 85c (30.0 g, 84.85 mmol) wasslowly added into 10 mL HCl/EA solution, stirring for 12 h at r.t. Thereaction solution was concentrated under reduced pressure to obtain thecrude product of 3-chloro-2-iodoaniline hydrochloride 85d (30.0 g,yellow solid).

¹H NMR (400 MHz, DMSO) δ 7.08 (t, J=8.0 Hz, 1H) 6.79 (d, J=7.5 Hz, 1H)6.73 d, J=8.0 Hz, 1H) 6.27 (br. s., 3H).

Step 4 tert-Butyl3-((3-chloro-2-iodophenyl)carbamoyl)azetidine-1-carboxylate

3-Chloro-2-iodoaniline hydrochloride 85c (28.0 g, 96.58 mmol) wasdissolved in 400 mL EA, 1-(tert-butoxycarbonyl)azetidine-3-carboxylicacid (23.3 g, 115.90 mmol), TEA (58.6 g, 579.48 mmol) and tripropylphosphoric anhydride (61.5 g, 193.16 mmol) were added at r.t., stirringfor 3 h at r.t. 500 mL H₂O was added, extracted with EA (500 mL×3),organic phases were combined and washed in sequence with water (500mL×2), saturated sodium chloride solution (500 mL×2), dried overanhydrous sodium sulfate, filtered, the filtrate was concentrated underreduced pressure to obtain the crude product of tert-butyl3-((3-chloro-2-iodophenyl)carbamoyl)azetidine-1-carboxylate 85e (26.5 g,white solid), yield: 71.1%.

¹H NMR (400 MHz, CDCl₃) δ 8.95 (d, J=7.4 Hz, 1H), 7.15 (t, J=7.6 Hz,2H), 4.11 (d, J=14.06 Hz, 4H), 3.17-3.02 (m, 1H), 1.38 (s, 9H).

Step 5 tert-Butyl3-((3-chloro-2-iodophenyl)(4-methoxybenzyl)carbamoyl)azetidine-1-carboxylate

tert-Butyl 3-((3-chloro-2-iodophenyl)carbamoyl)azetidine-1-carboxylate85e (30.0 g, 68.70 mmol) was dissolved in 200 mL DMF, cesium carbonate(26.9 g, 82.44 mmol), 1-chloromethyl-4-methoxybenzene (12.9 g, 82.44mmol) were added, stirring for 12 h at 90′C. 200 mL H₂O was added, themixture was extracted with EA (300 mL×3), organic phases were combinedand washed in sequence with water (300 mL×2), saturated sodium chloridesolution (300 mL×2), dried over anhydrous sodium sulfate, filtered, thefiltrate was concentrated under reduced pressure, the residue waspurified by silica gel column chromatography with eluting system C toobtain tert-butyl3-((3-chloro-2-iodophenyl)(4-methoxybenzyl)carbamoyl)azetidine-1-carboxylate85f (30.0 g, white solid), yield: 70.6%.

¹H NMR (400 MHz, CDCl₃) δ 7.72-7.62 (m, 1H), 7.11 (d, J=8.28 Hz, 2H),7.05-6.94 (m, 1H), 6.82 (d, J=8.28 Hz, 2H), 6.50-6.38 (m, 1H), 5.60-5.48(m, 1H), 4.36-4.24 (m, 1H), 4.03 (d, J=14.05 Hz, 2H), 3.81 (s, 3H),3.78-3.60 (m, 2H), 3.14-3.02 (m, 1H), 1.49-1.37 (m, 9H).

Step 6 tert-Butyl4′-chloro-1′-(4-methoxybenzyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate

tert-Butyl3-((3-chloro-2-iodophenyl)(4-methoxybenzyl)carbamoyl)azetidine-1-carboxylate85f (15.0 g, 26.94 mmol) was dissolved in 200 mL 1,4-dioxane, palladiumacetate (0.30 g, 1.35 mmol), sodium tert-butoxide (3.9 g, 40.41 mmol)were added at 21° C., the flask was swept with nitrogen gas,tricyclohexylphosphine (7.6 g, 26.94 mmol) was added dropwise at r.t.,stirring for 12 h at 110° C. The reaction solution was cooled to r.t.,filtered, the filter cake was washed with EA, the filtrate was combinedand concentrated under reduced pressure to obtain tert-butyl4′-chloro-1′-(4-methoxybenzyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate85g (6.0 g, yellow oil), yield: 46.7%.

¹H NMR (400 MHz, CDCl₃) δ 7.23 (d, J=8.8 Hz, 2H), 7.19-7.13 (m, 1H),7.04 (d, J=8.3 Hz, 1H), 6.90-6.83 (m, 2H), 6.69 (d, J=7.8 Hz, 1H),4.90-4.80 (m, 2H), 4.58 (br. s, 2H), 4.32 (d, J=8.3 Hz, 2H), 3.82-3.77(m, 3H), 1.51 (s, 9H).

Step 7 Isopropyl4′-chloro-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate

tert-Butyl4′-fluoro-1′-(4-methoxybenzyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate85g (6.0 g, 13.99 mmol) was dissolved in 120 mL trifluoroacetic acid,trifluoromethanesulfonic acid (6.3 g, 41.97 mmol) was added dropwise at0° C., stirring for 12 h at r.t. The reaction solution was concentratedunder reduced pressure, 60 mL THF and 60 mL H₂O were added into theresidue, sodium carbonate was added to adjust pH to 9˜10, isopropylchloroformate (12.3 g, 2.69 mmol) was added dropwise at 0° C., stirringfor 16 h at r.t. 100 mL H₂O was added, the mixture was extracted with EA(100 mL×3), organic phases were combined and washed in sequence withwater (100 mL×2), saturated sodium chloride solution (100 mL×2), driedover anhydrous sodium sulfate, filtered, the filtrate was concentratedunder reduced pressure, the residue was purified by silica gel columnchromatography with elution system C to obtain isopropyl4′-chloro-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate 85h (3.20g, white solid), yield: 67.9%.

¹H NMR (400 MHz, CDCl₃) δ 9.05 (br. s., 1H), 7.25-7.16 (m, 1H), 7.06 (d,J=8.03 Hz, 1H), 6.87 (d, J=8.03 Hz, 1H), 4.98 (spt, J=6.19 Hz, 1H), 4.59(d, J=8.53 Hz, 2H), 4.30 (d, J=8.03 Hz, 2H), 1.27 (d, J=6.02 Hz, 6H).

Step 8 Isopropyl4′-chloro-1′-(2,2-diethoxyethyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate

Isopropyl 4′-chloro-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate85h (2.0 g, 6.79 mmol), 2-bromo-1,1-diethoxyethane (1.6 g, 8.15 mmol),cesium carbonate (4.4 g, 13.6 mmol), potassium iodide (56.4 g, 0.34mmol) were dissolved in 25 mL DMF, stirring for 12 h at 90° C. 30 mL H₂Owas added into the reaction solution, the mixture was extracted with EA(20 mL×3), organic phases were combined and washed in sequence withwater (20 mL×2), saturated sodium chloride solution (20 mL×2), driedover anhydrous sodium sulfate, filtered, the filtrate was concentratedunder reduced pressure, the residue was purified by silica gel columnchromatography with elution system C to obtain isopropyl4′-chloro-1′-(2,2-diethoxyethyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate85i (2.2 g, yellow oil), yield: 97.0%.

¹H NMR (400 MHz, CDCl₃) δ 7.25-7.18 (m, 1H), 7.04 (d, J=8.0 Hz, 1H),6.97 (d, J=7.5 Hz, 1H), 4.97 (spt, J=6.2 Hz, 1H), 4.73-4.63 (m, 1H),4.56 (d, J=8.5 Hz, 2H), 4.27 (d, J=8.5 Hz, 2H), 3.81 (d, J=4.5 Hz, 2H),3.78-3.68 (m, 2H), 3.55-3.44 (m, 2H), 1.26 (d, J=6.5 Hz, 6H), 1.13 (t,J=7.0 Hz, 6H).

Step 9 Isopropyl4′-chloro-2′-oxo-1′-(2-oxoethyl)spiro[azetidine-3,3′-indoline]-1-carboxylate

Isopropyl4′-chloro-1′-(2,2-diethoxyethyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate85i (1.2 g, 2.92 mmol) was dissolved in 6 mL DCM and 2 mL H₂O,trifluoroacetic acid (0.33 g, 2.92 mmol) was added at 0° C., stirringfor 2 h at r.t., saturated sodium carbonate aqueous solution was addedto adjust pH to 9, the mixture was extracted with EA (150 mL×3), organicphases were combined and washed in sequence with water (80 mL×2),saturated sodium chloride solution (80 mL×2), dried over anhydroussodium sulfate, filtered, the filtrate was concentrated under reducedpressure to obtain the crude product of isopropyl4′-chloro-2′-oxo-1′-(2-oxoethyl)spiro[azetidine-3,3′-indoline]-1-carboxylate85j (0.9 g, yellow oil), yield: 91.5%.

¹H NMR (400 MHz, CDCl₃) δ 9.72 (t, J=8.0 Hz, 1H), 7.67 (d, J=8.0 Hz,1H), 7.25 (t, J=8.0 Hz, 1H) 6.97 (d, J=7.6 Hz, 1H), 4.73-4.63 (m, 1H),4.49 (d, 7.4 Hz, 2H) 4.25 (d, J=14.06 Hz, 4H), 1.32 (d, J=7.0 Hz, 6H).

Step 10 Isopropyl4′-chloro-2′-oxo-1′-((4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate

Isopropyl4′-chloro-2′-oxo-1′-(2-oxoethyl)spiro[azetidine-3,3′-indoline]-1-carboxylate85j (0.90 g, 2.67 mmol) was dissolved in 20 mL ethanol,1,2-cyclohexanedione (0.36 g, 3.21 mmol), ammonium acetate (1.03 g,13.36 mmol) were added, refluxing and stirring for 3 h. The reactionsolution was adjusted to pH 8-9 with saturated sodium carbonate aqueoussolution, extracted with EA (20 mL×3), organic phases were combined andwashed in sequence with saturated sodium bicarbonate aqueous solution(20 mL×2), saturated sodium chloride solution (30 mL×2), dried overanhydrous sodium sulfate, filtered, the filtrate was concentrated underreduced pressure, the residue was purified by silica gel columnchromatography with eluting system C to obtain isopropyl4′-chloro-2′-oxo-1′-(2-oxoethyl)spiro[azetidine-3,3′-indoline]-1-carboxylate85k (0.60 g, yellow oil), yield: 47.2%.

¹H NMR (400 MHz, CDCl₃) δ 7.29 (s, 1H), 7.22-7.17 (m, 1H), 7.07 (d,J=8.0 Hz, 1H), 4.98 (td, J=6.3 Hz, 12.6 Hz, 1H), 4.88 (d, J=2.5 Hz, 2H),4.56 (d, J=8.5 Hz, 2H), 4.27 (d, J=8.0 Hz, 2H), 2.51 (br. s, 4H), 1.77(br. s, 4H), 1.28 (t, J=6.0 Hz, 6H).

Step 11 Isopropyl4′-chloro-1′-((1-(4-hydroxybutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate

Isopropyl4′-chloro-2′-oxo-1′-(2-oxoethyl)spiro[azetidine-3,3′-indoline]-1-carboxylate85k (0.10 g, 0.48 mmol), 4-bromobutyl acetate (0.11 g, 0.58 mmol),cesium carbonate (0.31 g, 0.96 mmol) were dissolved in 10 mL DMF,stirring for 4 h at 80° C. The reaction solution was filtered and washedwith water, extracted with EA (20 mL×3), organic phases were combined,dried over anhydrous sodium sulfate, filtered, the filtrate wasconcentrated under reduced pressure, the residue was purified withsilica gel column chromatography with elution system C to obtain whitesolid. 10 mL 1M NaOH aqueous solution was added to dissolve, stirringfor 2 h at r.t. 30 mL water was added, the reaction solution wasextracted with EA (30 mL×2), washed in sequence with water (20 mL×2),saturated sodium chloride solution (20 mL×2), organic phases werecombined, dried over anhydrous sodium sulfate, filtered, the filtratewas concentrated under reduced pressure, preparative HPLC was used topurify and the target product isopropyl4′-chloro-1′-((1-(4-hydroxybutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate85 (13 mg, white solid), yield: 14.1%.

MS m/z (ESI): 501.3 [M+1]

¹H NMR (400 MHz, CDCl₃) δ 8.24 (br. s., 1H), 7.40 (d, J=8.03 Hz, 1H),7.26 (t, 0.1=8.00 Hz, 2H), 7.08 (d, J=8.03 Hz, 1H), 5.23-5.04 (m, 2H),4.97 (td, 0.1=6.27, 12.55 Hz, 1H), 4.57 (d, J=8.03 Hz, 2H), 4.27 (d,J=8.53 Hz, 2H), 3.95 (d, J=7.03 Hz, 2H), 3.73-3.64 (m, 2H), 2.97 (br.s., 4H), 2.63-2.43 (m, 4H), 1.79 (d, J=5.02 Hz, 4H), 1.28 (d, J=6.53 Hz,6H).

Embodiment 86 Isopropyl4′-chloro-2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate

Step 1 Isopropyl4′-chloro-2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate

Isopropyl 4′-chloro-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate86a (0.11 g, 0.38 mmol) was dissolved in 1 mL THF,(1-(4,4,4-trifluorobutyl)-4,5,6,7-86a 86tetrahydro-1H-benzo[d]imidazol-2-yl)methanol (0.10 g, 0.38 mmol),triphenylphosphine (0.12 g, 0.46 mmol) were added, diisopropylazodicarboxylate (92 mg, 0.46 mmol) in 1 mL THF was added dropwise at 0°C., stirring for 16 h at r.t. 30 mL H₂O was added, the mixture wasextracted with EA (20 mL×3), organic phases were combined and washed insequence with water (20 mL×2), saturated sodium chloride solution (20mL×2), dried over anhydrous sodium sulfate, filtered, the filtrate wasconcentrated under reduced pressure, preparative HPLC was used to purifyand the target product isopropyl4′-chloro-2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate86 (60 mg, white solid) was given, yield: 29.2%.

MS m/z (ESI): 539.1 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 7.28 (t, J=8.0 Hz, 1H), 7.12 (d, J=8.0 Hz,1H), 7.02 (d, J=7.5 Hz, 1H), 4.99 (s, 2H), 4.96-4.91 (m, 1H), 4.55 (m,2H), 4.26 (m, 2H), 4.05 (t, J=7.8 Hz, 2H), 2.53 (t, J=5.5 Hz, 2H), 2.46(t, J=5.8 Hz, 2H), 2.32-2.21 (m, 2H), 1.92-1.76 (m, 6H), 1.28 (d, J=6.0Hz, 6H).

Embodiment 87 Ethyl2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-1′,2′-dihydrospiro[azetidine-3,3′-pyrrolo[2,3-c]pyridine]-1-carboxylate

Step 1 tert-Butyl2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-1′,2′-dihydrospiro[azetidine-3,3′-pyrrolo[2,3-c]pyridine]-1-carboxylate

tert-Butyl2′-oxo-1′,2′-dihydrospiro[azetidine-3,3′-pyrrolo[2,3-c]pyridine]-1-carboxylate87a (0.94 g, 3.43 mmol) was dissolved in 10 mL THF,(1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methanol(0.9 g, 3.43 mmol), triphenylphosphine (1.08 g, 4.12 mmol) were added,diisopropyl azodicarboxylate (0.83 g, 4.12 mmol) was added dropwise at0° C., stirring for 16 h at r.t. 50 mL H₂O was added, the mixture wasextracted with EA (50 mL×3), organic phases were combined and washed insequence with water (50 mL×2), saturated sodium chloride solution (50mL×2), dried over anhydrous sodium sulfate, filtered, the filtrate wasconcentrated under reduced pressure, the residue was purified by silicagel column chromatography with eluting system C to obtain tert-butyl2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-1′,2′-dihydrospiro[azetidine-3,3′-pyrrolo[2,3-c]pyridine]-1-carboxylate87b (1.5 g, yellow oil), yield: 46.8%.

¹H NMR (400 MHz, CDCl₃) δ 8.80 (s, 1H), 8.50 (d, J=4.8 Hz, 1H), 7.50 (d,J=4.8 Hz, 1H), 5.04 (s, 2H), 4.36 (d, J=8.3 Hz, 2H), 4.05 (d, J=8.3 Hz,2H), 3.99-3.94 (m, J=7.8 Hz, 2H), 2.62-2.43 (m, 4H), 2.21-2.12 (m, 2H),1.85-1.74 (m, J=6.3 Hz, 6H), 1.50 (s, 9H).

Step 2 Ethyl2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-1′,2′-dihydrospiro[azetidine-3,3′-pyrrolo[2,3-c]pyridine]-1-carboxylate

tert-Butyl2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-1′,2′-dihydrospiro[azetidine-3,3′-pyrrolo[2,3-c]pyridine]-1-carboxylate87b (0.5 g, 0.962 mmol) was dissolved in 1 mL DCM, 3 mL trifluoroaceticacid was added, stirring for 2 h at r.t. The reaction solution wasconcentrated under reduced pressure, 3 mL THF and 1.5 mL H₂O were addedinto the residue, sodium carbonate was added to adjust pH to 9˜10, ethylchloroformate (0.16 g, 1.44 mmol) was added dropwise at 0° C., stirringfor 2 h at r.t. 100 mL water was added, the mixture was extracted withEA (100 mL×3), organic phases were combined and washed in sequence withwater (100 mL×2), saturated sodium chloride solution (100 mL×2), driedover anhydrous sodium sulfate, filtered, the filtrate was concentratedunder reduced pressure, preparative HPLC was used to purify and thetarget product ethyl2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-1′,2′-dihydrospiro[azetidine-3,3′-pyrrolo[2,3-c]pyridine]-1-carboxylate87 (125 mg, white solid) was given, yield: 26.4%.

MS m/z (ESI): 492.4 [M+1]

¹H NMR (400 MHz, CDCl₃) δ 8.42 (d, J=5.0 Hz, 1H), 8.27 (s, 1H), 7.77 (d,J=4.8 Hz, 1H), 5.06 (s, 2H), 4.37 (br. s., 2H), 4.21 (q, J=7.0 Hz, 4H),4.08 (t, J=7.9 Hz, 2H), 2.61-2.41 (m, 4H), 2.39-2.22 (m, J=8.5 Hz, 2H),1.93 (br. s., 2H), 1.89-1.75 (m, 4H), 1.31 (t, J=7.2 Hz, 3H).

Embodiment 88 Isopropyl2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-1′,2′-dihydrospiro[azetidine-3,3′-pyrrolo[2,3-c]pyridine]-1-carboxylate

Step 1 Isopropyl2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-1′,2′-dihydrospiro[azetidine-3,3′-pyrrolo[2,3-c]pyridine]-1-carboxylate

tert-Butyl2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-1′,2′-dihydrospiro[azetidine-3,3′-pyrrolo[2,3-c]pyridine]-1-carboxylate88a (0.1 g, 0.19 mmol) was dissolved in 1 mL DCM, 3 mL trifluoroaceticacid was added, stirring for 2 h at r.t. The reaction solution wasconcentrated under reduced pressure, 3 mL THF and 1.5 mL H₂O were addedinto the residue, sodium carbonate was added to adjust pH to 9˜10,isopropyl chloroformate (0.31 g, 1.44 mmol) was added dropwise at 0° C.,stirring for 2 h at r.t. 100 mL water was added, the mixture wasextracted with EA (30 mL×3), organic phases were combined and washed insequence with water (30 mL×2), saturated sodium chloride solution (30mL×2), dried over anhydrous sodium sulfate, filtered, the filtrate wasconcentrated under reduced pressure, preparative HPLC was used to purifyand the target product isopropyl2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-1′,2′-dihydrospiro[azetidine-3,3′-pyrrolo[2,3-c]pyridine]-1-carboxylate88 (36 mg, white solid) was given, yield: 29.2%.

MS m/z (ESI): 506.3 [M+1]

¹H NMR (400 MHz, CDCl₃) δ 8.40 (d, J=4.8 Hz, 1H), 8.25 (s, 1H), 7.75 (d,J=4.8 Hz, 1H), 5.04 (s, 2H), 4.97-4.92 (m, 1H), 4.35 (d, J=8.8 Hz, 2H),4.19 (d, J=8.5 Hz, 2H), 4.06 (t, 0.1=7.8 Hz, 2H), 2.55 (t, 0.1=8.0 Hz,2H), 2.46 (t, 0.1=5.5 Hz, 2H), 2.34-2.23 (m, 2H), 1.95-1.87 (m, 2H),1.87-1.76 (m, 4H), 1.29 (d, J=6.0 Hz, 6H).

Embodiment 891-(Cyclopropanecarbonyl)-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-pyrrolo[2,3-c]pyridine]-2′(1′H)-one

Step 11-(Cyclopropanecarbonyl)-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-pyrrolo[2,3-c]pyridine]-2′(1′H)-one

tert-Butyl2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-1′,2′-dihydrospiro[azetidine-3,3′-pyrrolo[2,3-c]pyridine]-1-carboxylate 89a (0.1 g, 0.19 mmol) was dissolved in 0.5mL DCM, 1.5 mL trifluoroacetic acid was added, stirring for 2 h at r.t.The reaction solution was concentrated under reduced pressure, 2 mL DCMwas added into the residue, TEA was added to adjust pH to 9˜10,cyclopropyl chloroformate (0.16 g, 1.44 mmol) was added dropwise at 0°C., stirring for 2 h at r.t. 30 mL water was added, the mixture wasextracted with EA (30 mL×3), organic phases were combined and washed insequence with water (30 mL×2), saturated sodium chloride solution (30mL×2), dried over anhydrous sodium sulfate, filtered, the filtrate wasconcentrated under reduced pressure, preparative HPLC was used to purifyand the target product1-(cyclopropanecarbonyl)-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-pyrrolo[2,3-c]pyridine]-2′(1′H)-one89 (22.5 mg, white solid), yield: 24.0%.

MS m/z (ESI): 488.2 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 8.43 (d, J=5.0 Hz, 1H), 8.28 (s, 1H), 7.79 (d,J=4.8 Hz, 1H), 5.08 (s, 2H), 4.74-4.67 (m, 1H), 4.64-4.61 (m, 1H), 4.37(d, J=9.8 Hz, 1H), 4.24 (d, J=9.8 Hz, 1H), 4.09 (t, J=7.8 Hz, 2H),2.64-2.44 (m, 4H), 2.38-2.26 (m, 2H), 1.94 (t, J=7.8 Hz, 2H), 1.87-1.80(m, 4H), 1.73-1.64 (m, J=4.8 Hz, 1H), 0.97-0.92 (m, 4H).

Embodiment 902′-Oxo-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate

Step 1 Benzyl 2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate

tert-Butyl1′-(4-methoxybenzyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate90a (50.0 g, 126.8 mmol) was dissolved in 250 mL trifluoroacetic acid,stirring for 0.5 h at 0° C., trifluoromethanesulfonic acid (57.1 g,380.3 mmol) was added dropwise at 0° C., stirring for 16 h at 0° C. Thereaction solution was concentrated under reduced pressure to give redoil, 100 mL THF and 100 mL H₂O were added into the residue, sodiumcarbonate was added to adjust pH to 9, phenol chloroformate (23.79 g,139.44 mmol) was added dropwise, stirring for 4 h at r.t. 1000 mL H₂Owas added, the mixture was extracted with EA (1000 mL×3), organic phaseswere combined and washed in sequence with water (1000 mL×2), saturatedsodium chloride solution (1000 mL×2), dried over anhydrous sodiumsulfate, filtered, the filtrate was concentrated under reduced pressure,the residue was purified by silica gel column chromatography withelution system C to obtain benzyl2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate 90b (22.0 g, yellowsolid), yield: 50.7%.

¹H NMR (400 MHz, CDCl₃) δ 8.69 (br. s., 1H), 7.51 (d, J=7.5 Hz, 1H),7.40-7.31 (m, 5H), 7.26 (t, J=7.3 Hz, 1H), 7.13 (t, J=7.3 Hz, 1H), 6.93(d, J=8.0 Hz, 1H), 5.18 (s, 2H), 4.47 (d, J=8.5 Hz, 2H), 4.18 (d, J=8.0Hz, 2H).

Step 2 Benzyl1′-(2,2-diethoxy)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate

Benzyl 2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate 90b (15.0 g,48.65 mmol) was dissolved in 100 mL DMF, cesium carbonate (31.7 g, 97.3mmol), 2-bromo-1,1-diethoxyethane (11.0 g, 55.95 mmol) were added,stirring for 3 h at 100° C. 300 mL saturated sodium carbonate aqueoussolution was added, the mixture was extracted with EA (300 mL×3),organic phases were combined and washed in sequence with water (300mL×2), saturated sodium chloride solution (300 mL×2), dried overanhydrous sodium sulfate, filtered, the filtrate was concentrated underreduced pressure, the residue was purified by silica gel columnchromatography with elution system C to obtain benzyl1′-(2,2-diethoxy)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate 90c(9.5 g, yellow oil), yield: 46.0%.

¹H NMR (400 MHz, CDCl₃) δ 7.52 (d, J=7.3 Hz, 1H), 7.43-7.29 (m, 6H),7.13 (t, J=8.0 Hz, 1H), 7.06 (d, J=7.8 Hz, 1H), 5.19 (s, 2H), 4.72 (t,J=5.4 Hz, 1H), 4.47 (d, J=8.3 Hz, 2H), 4.16 (d, J=8.3 Hz, 2H), 3.84 (d,J=5.3 Hz, 2H), 3.76 (qd, J=7.0, 9.2 Hz, 2H), 3.52 (qd, J=7.0, 9.3 Hz,2H), 1.15 (t, J=7.0 Hz, 6H).

Step 3 Benzyl2′-oxo-1′-(2-oxoethyl)spiro[azetidine-3,3′-indoline]-1-carboxylate

Benzyl1′-(2,2-diethoxy)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate 90c(9.5 g, 22.38 mmol) was dissolved in 100 mL DCM and 30 mL H₂O, 100 mLtrifluoroacetic acid was added dropwise, stirring for 2 h at r.t. 150 mLsaturated sodium carbonate aqueous solution was added, the mixture wasextracted with DCM (150 mL×3), organic phases were combined and washedin sequence with water (150 mL×2), saturated sodium chloride solution(150 mL×2), dried over anhydrous sodium sulfate, filtered, the filtratewas concentrated under reduced pressure to obtain benzyl2′-oxo-1′-(2-oxoethyl)spiro[azetidine-3,3′-indoline]-1-carboxylate 90d(7.0 g, yellow oil), yield: 89.3%.

¹H NMR (400 MHz, CDCl₃) δ 9.68 (s, 1H), 7.57 (d, J=7.0 Hz, 1H),7.45-7.27 (m, 6H), 7.13 (t, J=8.0 Hz, 1H), 6.65 (d, J=8.0 Hz, 1H), 5.18(s, 2H), 4.68-4.39 (m, 4H), 4.20 (d, J=8.5 Hz, 2H).

Step 4 Benzyl2′-oxo-1′-((4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate

Benzyl2′-oxo-1′-(2-oxoethyl)spiro[azetidine-3,3′-indoline]-1-carboxylate 90d(7.0 g, 19.98 mmol) was dissolved in 50 mL ethanol, 1,2-cyclohexanedione(2.69 g, 23.97 mmol), ammonium acetate (7.7 g, 99.9 mmol) were added,refluxing and stirring for 4 h. 150 mL saturated sodium carbonateaqueous solution was added, the mixture was extracted with EA (100mL×3), organic phases were combined and washed in sequence with water(100 mL×2), saturated sodium chloride solution (100 mL×2), dried overanhydrous sodium sulfate, filtered, the filtrate was concentrated underreduced pressure to obtain the crude product of benzyl2′-oxo-1′-((4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate90e (7.0 g, yellow solid).

¹H NMR (400 MHz, CDCl₃) δ 7.51 (d, J=7.5 Hz, 1H), 7.44-7.30 (m, 6H),7.21 (d, J=7.8 Hz, 1H), 7.14 (t, J=7.5 Hz, 1H), 5.18 (s, 2H), 4.87 (s,2H), 4.49-4.38 (m, 2H), 4.14 (d, J=7.8 Hz, 2H), 2.60-2.38 (br, 4H), 1.76(br. s., 4H).

Step 5 Benzyl2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate

Benzyl2′-oxo-1′-((4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate90e (7.0 g, 15.82 mmol) was dissolved in 50 mL DMF,4-bromo-1,1,1-trifluorobutane (3.32 g, 17.4 mmol), cesium carbonate(7.73 g, 23.73 mmol), potassium iodide (0.131 g, 0.791 mmol) were added,stirring for 3 h at 90° C. 100 mL H₂O was added, the mixture wasextracted with EA (100 mL×3), organic phases were combined and washed insequence with water (100 mL×2), saturated sodium chloride solution (100mL×2), dried over anhydrous sodium sulfate, filtered, the filtrate wasconcentrated under reduced pressure, the residue was purified by silicagel column chromatography with elution system C to obtain benzyl2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate90f (4.8 g, yellow solid), yield: 52.2%.

¹H NMR (400 MHz, CDCl₃) δ 7.57 (d, J=7.8 Hz, 1H), 7.50 (d, J=7.3 Hz,1H), 7.40-7.30 (m, 6H), 7.16 (t, J=8.0 Hz, 1H), 5.17 (s, 2H), 4.96 (s,2H), 4.42 (d, J=8.4 Hz, 2H), 4.13 (d, J=8.4 Hz, 2H), 3.97 (t, J=7.8 Hz,2H), 2.61-2.51 (br, 2H), 2.49-2.38 (br, 2H), 2.24-2.09 (m, 2H),1.83-1.75 (m, 6H).

Step 62′-Oxo-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate

Benzyl2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate90f (0.2 g, 0.36 mmol) was dissolved in 2 mL ethanol, ammonium formate(22.8 mg, 0.36 mmol), Pd/C (20 mg) were added, stirring for 16 h at r.t.30 mL H₂O was added, the mixture was extracted with EA (30 mL×3),organic phases were combined and washed in sequence with water (30mL×2), saturated sodium chloride solution (30 mL×2), dried overanhydrous sodium sulfate, filtered, the filtrate was concentrated underreduced pressure, preparative HPLC was used to purify and the targetproduct2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate90 (34.5 mg, white solid) was given, yield: 77.3%.

MS m/z (ESI): 447.2 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 8.14 (s, 1H), 7.66 (d, J=7.28 Hz, 1H),7.28-7.35 (m, 1H), 7.16-7.23 (m, 1H), 7.08 (d, J=7.78 Hz, 1H), 5.02 (s,2H), 4.61 (d, J=8.78 Hz, 1H), 4.48 (d, J=8.78 Hz, 1H), 4.39 (d, J=10.04Hz, 1H), 4.23 (d, J=10.04 Hz, 1H), 4.07 (t, 0.1=7.91 Hz, 2H), 2.45-2.59(m, 4H), 2.20-2.35 (m, 2H), 1.76-1.94 (m, 6H).

Embodiment 911-(1-Methylcyclopropane-1-carbonyl)-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-pyrrole[2,3-c]pyridine]-2′-one

Step 11′-((1-(4,4,4-Trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one

tert-Butyl1′-oxo-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate91a (0.1 g, 0.19 mmol) was dissolved in 1 mL DCM, 0.5 mL trifluoroaceticacid was added, stirring for 0.5 h at r.t. 30 mL 1N NaOH aqueoussolution was added, the mixture was extracted with DCM (30 mL×3),organic phases were combined and washed in sequence with water (30mL×2), saturated sodium chloride solution (30 mL×2), dried overanhydrous sodium sulfate, filtered, the filtrate was concentrated underreduced pressure to obtain the crude product1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one91b (110, yellow solid).

¹H NMR (400 MHz, CDCl₃) δ 7.77 (d, J=7.28 Hz, 1H), 7.53 (d, J=7.78 Hz,1H), 7.36-7.29 (m, 1H), 7.18 (t, J=7.40 Hz, 1H), 4.98 (s, 2H), 4.23 (d,J=7.78 Hz, 2H), 4.00 (t, J=6.78 Hz, 2H), 3.74 (d, J=8.00 Hz, 2H), 2.59(br. s., 2H), 2.46 (br. s., 2H), 2.24-2.09 (m, 2H), 1.81 (d, J=4.77 Hz,2H), 1.69-1.51 (m, 2H), 1.49-1.36 (m, 2H).

Step 21-(1-Methylcyclopropane-1-carbonyl)-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-pyrrole[2,3-c]pyridine]-2′-one

1′-((1-(4,4,4-Trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one91b (110 mg, 0.26 mmol) was dissolved in 1 mL EA,1-methylcyclopropanecarboxylic acid (32 mg, 0.32 mmol), TEA (53 mg, 0.53mmol) were added, tripropyl phosphorous acid anhydride (251 mg, 0.39mmol) was added dropwise, stirring for 16 h at r.t. 30 mL 1N NaOHaqueous solution was added, the mixture was extracted with EA (30 mL×3),organic phases were combined and washed in sequence with 1N NaOH aqueoussolution (30 mL×2), 0.1N HCl aqueous solution (30 mL×2), saturatedsodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate,filtered, the filtrate was concentrated under reduced pressure,preparative HPLC was used to purify and1-(1-methylcyclopropane-1-carbonyl)-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-pyrrole[2,3-c]pyridine]-2′-one91c (60 mg, white solid), yield: 45.6%.

MS m/z (ESI): 501.4 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 7.66 (d, J=7.53 Hz, 1H), 7.35-7.29 (m, 1H),7.24-7.17 (m, 1H), 7.10 (d, J=7.78 Hz, 1H), 5.05 (s, 2H), 4.84-4.64 (m,2H), 4.38 (br. s., 1H), 4.18 (br. s., 1H), 4.09 (t, J=7.78 Hz, 2H),2.59-2.48 (m, 4H), 2.29 (dd, J=10.54, 16.31 Hz, 2H), 1.91-1.78 (m, 6H),1.40 (s, 3H), 1.14 (br. s., 2H), 0.65 (d, J=2.26 Hz, 2H).

Embodiment 921-Acetyl-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one

Step 11-Acetyl-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one

1′-((1-(4,4,4-Trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one92a (150 mg, 0.36 mmol) was dissolved in 5 mL DCM, TEA (70 mg, 0.69mmol) was added, acetyl chloride (40 mg, 0.51 mmol) was added dropwise,stirring for 1 h at r.t. 30 mL water was added, the mixture wasextracted with EA (30 mL×3), organic phases were combined and washed insequence with water (30 mL×2), saturated sodium chloride solution (30mL×2), dried over anhydrous sodium sulfate, filtered, the filtrate wasconcentrated under reduced pressure, preparative HPLC was used to purifyand the target product1-acetyl-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one92 (4 mg, white solid) was given, yield: 2.4%.

MS m/z (ESI): 461.2 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 7.73 (br. s., 1H), 7.39 (br. s., 1H), 7.27(br. s., 1H), 7.06 (br. s., 1H), 5.26 (br. s., 2H), 4.46-4.62 (m, 2H),4.37 (d, J=9.54 Hz, 1H), 4.24 (br. s., 3H), 2.52-2.72 (m, 4H), 2.38 (d,J=4.77 Hz, 2H), 2.02 (br. s., 5H), 1.90 (d, J=5.52 Hz, 4H).

Embodiment 931-(Cyclopropanecarbonyl)-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one

Step 11-(Cyclopropanecarbonyl)-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one

1′-((1-(4,4,4-Trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one93a (125 mg, 0.30 mmol) was dissolved in 5 mL DCM, TEA (45 mg, 0.45mmol) was added, cyclopropionyl chloride (37 mg, 0.36 mmol) was addeddropwise, stirring for 4 h at r.t. 30 mL water was added, the mixturewas extracted with EA (30 mL×3), organic phases were combined and washedin sequence with water (30 mL×2), saturated sodium chloride solution (30mL×2), dried over anhydrous sodium sulfate, filtered, the filtrate wasconcentrated under reduced pressure, preparative HPLC was used to purifyand the target product1-(cyclopropanecarbonyl)-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one93 (35 mg, white solid), yield: 24.1%.

MS m/z (ESI): 487.4 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 7.66 (d, J=7.28 Hz, 1H), 7.35-7.28 (m, 1H),7.24-7.17 (m, 1H), 7.10 (d, J=7.78 Hz, 1H), 5.03 (s, 2H), 4.70 (d,J=8.78 Hz, 1H), 4.57 (d, J=8.53 Hz, 1H), 4.37 (d, J=9.54 Hz, 1H), 4.19(d, J=9.54 Hz, 1H), 4.08 (t, J=7.78 Hz, 2H), 2.58-2.46 (m, 4H),2.35-2.21 (m, 2H), 1.93-1.77 (m, 6H), 1.73-1.65 (m, 1H), 1.03-0.87 (m,4H).

Embodiment 941-Propionyl-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one

Step 11-Propionyl-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one

1′-((1-(4,4,4-Trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one94a (0.6 g, 0.72 mmol) was dissolved in 10 mL DCM, TEA (0.21 g, 2.15mmol) was added, propionyl chloride (0.13 g, 1.43 mmol) was addeddropwise, stirring for 1 h at r.t. 100 mL water was added, the mixturewas extracted with EA (100 mL×3), organic phases were combined andwashed in sequence with water (100 mL×2), saturated sodium chloridesolution (100 mL×2), dried over anhydrous sodium sulfate, filtered, thefiltrate was concentrated under reduced pressure, preparative HPLC wasused to purify and the target product1-propionyl-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one94 (60 mg, white solid) was given, yield: 17.6%.

MS m/z (ESI): 475.2 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 7.63 (d, J=7.3 Hz, 1H), 7.33-7.26 (m, 1H),7.21-7.14 (m, 1H), 7.07 (d, J=7.8 Hz, 1H), 5.00 (s, 2H), 4.54 (d, J=8.8Hz, 1H), 4.43 (d, J=8.5 Hz, 1H), 4.34 (d, J=9.5 Hz, 1H), 4.17 (d, J=9.8Hz, 1H), 4.05 (t, J=7.8 Hz, 2H), 2.57-2.50 (m, 2H), 2.48 (t, J=5.4 Hz,2H), 2.34-2.19 (m, 4H), 1.91-1.73 (m, 6H), 1.16 (t, J=7.5 Hz, 3H).

Embodiment 951-Isobutyryl-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one

Step 11-Isobutyryl-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one

1′-((1-(4,4,4-Trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one95a (0.1 g, 0.24 mmol) was dissolved in 10 mL DCM, TEA (73 mg, 0.72mmol) was added, 2-methyl propionylchloride (38 mg, 0.36 mmol) was addeddropwise, stirring for 1 h at r.t. 30 mL water was added, the mixturewas extracted with EA (30 mL×3), organic phases were combined and washedin sequence with water (30 mL×2), saturated sodium chloride solution (30mL×2), dried over anhydrous sodium sulfate, filtered, the filtrate wasconcentrated under reduced pressure, preparative HPLC was used to purifyand the target product1-isobutyryl-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one95 (30 mg, white solid), yield: 24.9%.

MS m/z (ESI): 489.3 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 7.61 (d, J=8.03 Hz, 1H), 7.49 (d, J=7.28 Hz,1H), 7.37 (t, J=7.78 Hz, 1H), 7.21-7.15 (m, 1H), 5.05-4.92 (m, 2H), 4.56(d, J=8.03 Hz, 1H), 4.41 (d, J=9.29 Hz, 1H), 4.28 (d, J=7.78 Hz, 1H),4.18 (d, J=9.54 Hz, 1H), 4.10-3.91 (m, 2H), 2.63-2.44 (m, 5H), 2.31-2.05(m, 2H), 1.81 (br. s., 6H), 1.20 (d, J=6.78 Hz, 6H).

Embodiment 961-(2,2-Difluoroacetyl)-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one

Step 11-(2,2-Difluoroacetyl)-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one

1′-((1-(4,4,4-Trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one96a (0.1 g, 0.24 mmol) was dissolved in 2 mL EA, TEA (48 mg, 0.478mmol), difluoroacetic acid (23 mg, 0.24 mmol), tripropyl phosphorousacid anhydride (0.23 g, 0.36 mmol) were added, stirring for 1.5 h atr.t. 30 mL water was added, the mixture was extracted with EA (30 mL×3),organic phases were combined and washed in sequence with water (30mL×2), saturated sodium chloride solution (30 mL×2), dried overanhydrous sodium sulfate, filtered, the filtrate was concentrated underreduced pressure, preparative HPLC was used to purify and the targetproduct1-(2,2-difluoroacetyl)-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one96 (22 mg, white solid), yield: 18.2%.

MS m/z (ESI): 519.3 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 7.68 (d, J=7.0 Hz, 1H), 7.30 (t, J=8.0 Hz,1H), 7.18 (t, J=8.0 Hz, 1H), 7.05 (d, J=7.5 Hz, 1H), 6.26 (t, J=52.0 Hz,1H), 5.00 (s, 2H), 4.77 (d, J=9.5 Hz, 1H), 4.64 (d, J=9.5 Hz, 1H), 4.45(d, J=10.5 Hz, 1H), 4.31 (d, J=10.5 Hz, 1H), 4.06 (t, J=8.0 Hz, 2H),2.54 (t, J=8.0 Hz, 2H), 2.47 (t, J=8.0 Hz, 2H), 2.27 (m, 2H), 1.92-1.75(m, 6H).

Embodiment 971-(Methylsulfonyl)-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one

Step 11-(Methylsulfonyl)-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one

1′-((1-(4,4,4-Trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one97a (0.1 g, 0.24 mmol) was dissolved in 2 mL DCM, TEA (24 mg, 0.24 mmol)was added, methanesulfonyl chloride (50 mg, 0.44 mmol) was addeddropwise, stirring for 2 h at r.t. 30 mL Saturated sodium carbonateaqueous solution was added, the mixture was extracted with EA (30 mL×3),organic phases were combined and washed in sequence with water (30mL×2), saturated sodium chloride solution (30 mL×2), dried overanhydrous sodium sulfate, filtered, the filtrate was concentrated underreduced pressure, preparative HPLC was used to purify and the targetproduct1-(methylsulfonyl)-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one97 (25 mg, white solid) was given, yield: 21.1%.

MS m/z (ESI): 497.3 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 7.72 (d, J=7.28 Hz, 1H), 7.29-7.35 (m, 1H),7.18-7.25 (m, 1H), 7.07 (d, J=7.78 Hz, 1H), 5.01 (s, 2H), 4.38 (d,J=8.53 Hz, 2H), 4.14 (d, J=8.28 Hz, 2H), 4.03-4.11 (m, 2H), 3.15 (s,3H), 2.45-2.59 (m, 4H), 2.24-2.35 (m, 2H), 1.77-1.94 (m, 6H).

Embodiment 98 1-(Cyclopropylsulfonyl)-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one

Step 1 1-(Cyclopropylsulfonyl)-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one

1′-((1-(4,4,4-Trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one98a (0.12 g, 0.29 mmol) was dissolved in 2 mL DCM, TEA (87 mg, 0.86mmol) was added, cyclopropanesulfonyl chloride (48 mg, 0.34 mmol) wasadded dropwise, stirring for 2 h at r.t. 30 mL water was added, themixture was extracted with EA (30 mL×3), organic phases were combinedand washed in sequence with water (30 mL×2), saturated sodium chloridesolution (30 mL×2), dried over anhydrous sodium sulfate, filtered, thefiltrate was concentrated under reduced pressure, preparative HPLC wasused to purify and the target product 1-(cyclopropylsulfonyl)-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one98 (35.6 mg, white solid) was given, yield: 22.6%.

MS m/z (ESI): 523.4 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 7.73 (d, J=7.0 Hz, 1H), 7.36-7.27 (m, 1H),7.25-7.15 (m, 1H), 7.12-6.99 (m, 1H), 5.01 (s, 2H), 4.47 (d, J=8.0 Hz,2H), 4.14 (d, J=8.0 Hz, 2H), 4.07 (t, J=7.8 Hz, 2H), 2.80 (t, J=5.0 Hz,1H), 2.62-2.43 (m, 4H), 2.37-2.21 (m, J=5.5 Hz, 2H), 2.02-1.63 (m, J=8.0Hz, 6H), 1.23-1.10 (m, 4H).

Embodiment 99 1-(Isopropylsulfonyl)-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one

Step 11-(Isopropylsulfonyl)-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one

1′-((1-(4,4,4-Trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one99a (0.38 g, 0.91 mmol) was dissolved in 4 mL DCM, TEA (0.46 g, 4.54mmol) was added, isopropanesulfonyl chloride (0.39 g, 2.72 mmol) wasadded dropwise at 0° C., stirring for 3 h at r.t. 50 mL water was added,the mixture was extracted with EA (50 mL×3), organic phases werecombined and washed in sequence with water (50 mL×2), saturated sodiumchloride solution (50 mL×2), dried over anhydrous sodium sulfate,filtered, the filtrate was concentrated under reduced pressure,preparative HPLC was used to purify and the target product1-(isopropylsulfonyl)-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one99 (5 mg, white solid), yield: 1.05%.

MS m/z (ESI): 525.3 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 7.68 (d, J=7.3 Hz, 1H), 7.30 (t, J=8.0 Hz,1H), 7.19 (t, J=8.0 Hz, 1H), 7.07 (d, J=8.0 Hz, 1H), 4.99 (s, 2H), 4.94(m., 1H), 4.38 (d, J=7.8 Hz, 2H), 4.11 (d, J=8.0 Hz, 2H), 4.05 (t, J=8.0Hz, 2H), 2.53 (t, J=8.0 Hz, 2H), 2.47 (t, J=5.5 Hz, 2H), 2.33-2.19 (m,2H), 1.89-1.74 (m, 6H), 1.41 (d, J=6.8 Hz, 6H).

Embodiment 100 Isopropyl 1′-((1-(4-hydroxybutyl)-4,5-dimethyl-1H-imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate

Step 1 Isopropyl2′-oxo-1′-(2-oxoethyl)spiro[azetidine-3,3′-indoline]-1-carboxylate

Isopropyl1′-(2,2-diethoxyethyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate100a (0.60 g, 1.59 mmol) was dissolved in 4.5 mL DCM and 1.5 mL H₂O, 4.5mL trifluoroacetic acid was added at 0° C., stirring for 1 h at r.t.under nitrogen gas atmosphere. Potassium carbonate was added toneutralize the reaction solution, the mixture was extracted with DCM (15mL×3), organic phases were combined and washed in sequence with water(15 mL×2), saturated sodium chloride solution (15 mL×2), dried overanhydrous sodium sulfate, filtered, the filtrate was concentrated underreduced pressure to obtain the crude product isopropyl2′-oxo-1′-(2-oxoethyl)spiro[azetidine-3,3′-indoline]-1-carboxylate 100b(0.41 g, yellow oil), yield: 75.9%.

Step 2 Isopropyl1′-((4,5-dimethyl-1H-imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate

Isopropyl2′-oxo-1′-(2-oxoethyl)spiro[azetidine-3,3′-indoline]-1-carboxylate 100b(0.90 g, 2.67 mmol) was dissolved in 5 mL ethanol, 2,2-butanedione (0.14g, 1.58 mmol), ammonium acetate (0.51 g, 6.6 mmol) were added, stirringat reflux for 4 h under nitrogen gas atmosphere. The reaction solutionwas cooled to r.t., extracted with EA (20 mL×3), organic phases werecombined and washed in sequence with water (15 mL×2), saturated sodiumchloride solution (15 mL×2), dried over anhydrous sodium sulfate,filtered, the filtrate was concentrated under reduced pressure, theresidue was purified by silica gel column chromatography with elutingsystem C to obtain isopropyl1′-((4,5-dimethyl-1H-imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate100c (0.60 g, white solid), yield: 74.0%.

MS m/z (ESI): 369.1 [M+1]

Step 3 Isopropyl 1′-((1-(4-hydroxybutyl)-4,5-dimethyl-1H-imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate

Isopropyl 1′-((4,5-dimethyl-1H-imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate100c (0.36 g, 0.98 mmol) was dissolved in 5 mL acetonitrile,4-bromobutyl acetate (0.23 g, 1.17 mmol), potassium carbonate (0.14 g,0.98 mmol) and potassium iodide (0.16 g, 0.98 mmol) were added, thereaction mixture was heated to reflux and stirred for 18 h undernitrogen gas atmosphere. The reaction solution was filtered, washed withwater, extracted with EA (20 mL×3), organic phases were combined andwashed in sequence with water (15 mL×2), saturated sodium chloridesolution (15 mL×2), dried over anhydrous sodium sulfate, filtered, thefiltrate was concentrated under reduced pressure to obtain yellow solid.3 mL 1M NaOH aqueous solution was added to dissolve, stirring for 1 h atr.t. 30 mL water was added into the reaction solution, the mixture wasextracted with EA (30 mL×2), organic phases were combined and washed insequence with water (20 mL×2), saturated sodium chloride solution (20mL×2), dried over anhydrous sodium sulfate, filtered, the filtrate wasconcentrated under reduced pressure, preparative HPLC was used to purifyand the target product isopropyl 1′-((1-(4-hydroxybutyl)-4,5-dimethyl-1H-imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate100 (0.14 g, white solid) was given, yield: 47.5%.

MS m/z (ESI): 441.1 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 7.63 (d, J=7.6 Hz, 1H), 7.41-6.95 (m, 3H),4.99 (s, 2H), 4.70 (s, 1H), 4.36 (s, 2H), 4.18 (s, 2H), 3.99 (t, J=6.8Hz, 2H), 3.58 (t, J=6 Hz, 2H), 2.15 (s, 3H), 2.07 (s, 3H), 1.64-1.57 (m,4H), 1.31 (t, J=6 Hz, 6H).

Embodiment 101 Ethyl 1′-((4,5-diethyl-1-(4-hydroxybutyl)-1H-imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate

Step 1 Ethyl2′-oxo-1′-(2-oxo-2-((4-oxobutyl-3-yl)oxy)ethyl)spiro[azetidine-3,3′-indoline]-1-carboxylate

2-(1-(Ethoxycarbonyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate101a (1.00 g, 3.29 mmol) was dissolved in 5 mL DCM, oxalyl chloride(1.67 g, 13.16 mmol) was added, stirring for 1 h at r.t., 4-hydroxyhexane-3-one (0.46 g, 3.94 mmol) in 5 mL DCM was added, stirring for 3 hat r.t. 50 mL water was added into the reaction solution, the mixturewas extracted with EA (50 mL×3), organic phases were combined and washedin sequence with water (50 mL×2), saturated sodium chloride solution (50mL×2), dried over anhydrous sodium sulfate, filtered, the filtrate wasconcentrated under reduced pressure, the residue was purified by silicagel column chromatography with eluting system C to obtain ethyl2′-oxo-1′-(2-oxo-2-((4-oxobutyl-3-yl)oxy)ethyl)spiro[azetidine-3,3′-indoline]-1-carboxylate101b (0.09 g, yellow oil), yield: 61.2%.

¹H NMR (400 MHz, CDCl₃) δ 7.56 (d, J=7.5 Hz, 1H), 7.35 (t, N=7.8 Hz,1H), 7.17 (t, J=7.5 Hz, 1H), 6.84 (d, J=7.5 Hz, 1H), 5.05 (dd, J=4.3,7.8 Hz, 1H), 4.71 (d, J=17.6 Hz, 1H), 4.53-4.40 (m, 3H), 4.24-4.12 (m,4H), 2.43 (dq, J=1.5, 7.2 Hz, 2H), 1.94-1.71 (m, 2H), 1.29 (t, J=7.3 Hz,3H), 1.05 (t, J=7.0 Hz, 6H), 0.92 (t, J=7.3 Hz, 3H).

Step 2 ethyl1′-((4,5-diethyl-1H-imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate

Ethyl2′-oxo-1′-(2-oxo-2-((4-oxobutyl-3-yl)oxy)ethyl)spiro[azetidine-3,3′-indoline]-1-carboxylate101b (0.80 g, 1.99 mmol) was dissolved in 4 m xylene, ammonium acetate(1.53 g, 19.88 mmol) was added, reacting for 40 min under 16° C.microwave. 10 mL water was added into the reaction mixture, the mixturewas extracted with EA (10 mL×3), organic phases were combined and washedin sequence with water (10 mL×2), saturated sodium chloride solution (10mL×2), dried over anhydrous sodium sulfate, filtered, the filtrate wasconcentrated under reduced pressure, the residue was purified by thinlayer chromatography with eluting system C to obtain isopropyl1′-((4,5-dimethyl-1H-imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate101c (60 mg, yellow oil), yield: 7.1%.

¹H NMR (400 MHz, CDCl₃) δ 7.53 (d, J=7.0 Hz, 1H), 7.36-7.30 (m, 2H),7.15 (t, J=7.3 Hz, 1H), 4.90 (s, 1H), 4.40 (d, J=8.0 Hz, 2H), 4.23-4.17(q, J=7.2 Hz, 2H), 4.12 (d, J=8.0 Hz, 2H), 2.53-2.47 (q, J=7.6 Hz, 4H),1.30 (t, J=7.6 Hz, 3H), 1.17 (t, J=7.6 Hz, 6H).

Step 3 Ethyl 1′-((1-(4-hydroxybutyl)-4,5-diethyl-1H-imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate

Isopropyl1′-((4,5-diethyl-1H-imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate101c (70 mg, 0.18 mmol) was dissolved in 5 mL DMF, 4-bromobutyl acetate(107 mg, 0.55 mmol), cesium carbonate (179 mg, 0.55 mmol) and potassiumiodide (3.0 mg, 0.01 mmol) were added at 90° C., and the reactionmixture was stirred for 20 h at 90° C. The reaction solution wasfiltered, washed with water, extracted with EA (20 mL×3), organic phaseswere combined and washed in sequence with water (15 mL×2), saturatedsodium chloride solution (15 mL×2), dried over anhydrous sodium sulfate,filtered, the filtrate was concentrated under reduced pressure, theresidue was purified by thin layer chromatography with eluting system Cto obtain yellow oil. 3 mL 1M NaOH aqueous solution was added todissolve, stirring for 0.5 h at r.t. 30 mL water was added into thereaction solution, the mixture was extracted with EA (20 mL×3), organicphases were combined and washed in sequence with water (20 mL×2),saturated sodium chloride solution (20 mL×2), dried over anhydroussodium sulfate, filtered, the filtrate was concentrated under reducedpressure, preparative HPLC was used to purify and the target productethyl 1′-((1-(4-hydroxybutyl)-4,5-diethyl-1H-imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate101 (7 mg, white solid) was given, yield: 38.2%.

MS m/z (ESI): 455.3 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 7.60 (d, J=7.3 Hz, 1H), 7.28-7.21 (t, J=7.92Hz, 1H), 7.17-7.11 (t, J=7.92 Hz, 1H), 7.00 (d, J=7.8 Hz, 1H), 4.97 (s,2H), 4.35 (d, J=8.1 Hz, 2H), 4.16 (q, J=7.1 Hz, 4H), 3.97 (d, J=8.1 Hz,2H), 3.55 (t, J=6.0 Hz, 2H), 2.57 (q, J=7.6 Hz, 2H), 2.44 (q, J=7.6 Hz,2H), 1.67-1.45 (m, 4H), 1.28 (t, J=7.1 Hz, 4H), 1.11 (dt, J=4.2, 7.6 Hz,6H).

Embodiment 102 Isopropyl2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-1,4,5,6-tetrahydrocyclopenta[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate

Step 1 2-Bromocyclopentan-1-one

Cyclopentanone 102a (5.04 g, 59.9 mmol) and p-toluene sulfonic acid(1.14 g, 5.99 mmol) were added into the flask with three necks,N-bromosuccinimide (10.66 g, 59.9 mmol) was added in portions at 0° C.,stirring for 2 h at r.t. 200 mL water was added, the mixture wasextracted with EA (200 mL×3), organic phases were combined and washed insequence with water (200 mL×2), saturated sodium chloride solution (200mL×2), dried over anhydrous sodium sulfate, filtered, the filtrate wasconcentrated under reduced pressure, the residue was purified by silicagel column chromatography with eluting system C to obtain2-bromocyclopentan-1-one 102b (7.6 g, light yellow liquid), yield:62.3%.

¹H NMR (400 MHz, CDCl₃) δ 4.26-4.18 (m, 1H), 2.45-2.35 (m, 2H),2.28-2.16 (m, 3H), 2.07-1.98 (m, 1H).

Step 2 2-hydroxycyclopenta-2-en-1-one

2-Bromocyclopentan-1-one 102b (0.84 g, 5.14 mmol) was dissolved into 10mL H₂O (preheated to 98° C.), 10 mL FeCl₃ (1.65 g, 10.17 mmol) in H₂O(preheated to 80° C.) was added, stirring for 10 min at 98° C. Thereaction solution was cooled to 40° C., 10 mL saturated ammonium sulfateaqueous solution was added, the mixture was extracted with EA (200mL×3), organic phases were combined and washed in sequence with water(200 mL×2), saturated sodium chloride solution (200 mL×2), dried overanhydrous sodium sulfate, filtered, the filtrate was concentrated underreduced pressure to obtain the crude product2-hydroxycyclopenta-2-en-1-one 102c (0.24 g, yellow oil).

¹H NMR (400 MHz, CDCl₃) δ 6.57 (t, J=3.0 Hz, 1H), 5.65 (br. s., 1H),2.54-2.50 (m, 2H), 2.47-2.43 (m, 2H).

Step 3 Isopropyl 2′-oxo-1′-((1,4,5,6-tetrahydrocyclopenta[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate

2-Hydroxycyclopenta-2-en-1-one 102c (85 mg, 0.87 mmol) was dissolved in4 mL ethanol, isopropyl2′-oxo-1′-(2-ethoxy)-spiro[azetidine-3,3′-indoline]-1-carboxylate (0.26g, 0.87 mmol), ammonium carbonate (0.33 g, 4.33 mmol) were added,stirring for 2 h at 80′C. The reaction solution was concentrated underreduced pressure, 20 mL saturated sodium carbonate aqueous solution wasadded, the mixture was extracted with EA (20 mL×3), organic phases werecombined and washed in sequence with water (20 mL×2), saturated sodiumchloride solution (20 mL×2), dried over anhydrous sodium sulfate,filtered, the filtrate was concentrated under reduced pressure, theresidue was purified by silica gel column chromatography with elutingsystem C to obtain isopropyl2′-oxo-1′-((1,4,5,6-tetrahydrocyclopenta[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate102d (50 mg, yellow solid).

¹H NMR (400 MHz, CD₃OD) δ 7.53 (d, J=7.0 Hz, 1H), 7.36-7.32 (m, 2H),7.15 (d, J=8.0 Hz, 1H), 4.97 (m, 1H), 4.90 (s, 2H), 4.39 (d, J=8.0 Hz,2H), 4.12 (d, J=8.0 Hz, 2H), 2.69-2.58 (m, 4H), 2.47-2.41 (m, 2H), 1.29(d, J=4.0 Hz, 6H).

Step 4 Isopropyl2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-1,4,5,6-tetrahydrocyclopenta[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate

Isopropyl2′-oxo-1′-((1,4,5,6-tetrahydrocyclopenta[d]imidazol-2-yl)methyl)-2′,3′-dihydrospiro[azetidine-3,1′-indene]-1-carboxylate 102d (50 mg, 0.13 mmol) was dissolved in 1 mLDMF, 4-bromo-1,1,1-trifluorobutane (30 mg, 0.16 mmol), cenium carbonate(85 mg, 0.26 mmol) were added, stirring for 2 h at 80′C. The reactionsolution was cooled to r.t., 30 mL water was added, extracted with EA(30 mL×2), organic phases were combined and washed with saturated sodiumchloride solution (20 mL×2), dried over anhydrous sodium sulfate,filtered, the filtrate was concentrated under reduced pressure,preparative HPLC was used to purify and the target product isopropyl2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-1,4,5,6-tetrahydrocyclopenta[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate102 (7.5 mg, white solid) was given, yield: 11.6%.

MS m/z (ESI): 491.3 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 7.62 (d, J=7.5 Hz, 1H), 7.29 (t, J=8.0 Hz,1H), 7.17 (t, J=8.0 Hz, 1H), 7.12 (d, J=7.5 Hz, 1H), 4.99 (s, 2H),4.94-4.93 (m, 1H), 4.33 (d, J=8.0 Hz, 2H), 4.15 (d, J=8.0 Hz, 2H), 4.09(t, J=7.5 Hz, 2H), 2.70 (t, J=6.8 Hz, 2H), 2.59-2.56 (m, 2H), 2.52-2.45(m, 2H), 2.24-2.17 (m, 2H), 1.94-1.86 (m, 2H), 1.29 (d, J=6.5 Hz, 6H).

Embodiment 103 Isopropyl1′-((1-(4-hydroxybutyl)-1,4,5,6-tetrahydrocyclopenta[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate

Step 1 Isopropyl1′-((1-(4-hydroxybutyl)-1,4,5,6-tetrahydrocyclopenta[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate

Isopropyl2′-oxo-3′-((1,4,5,6-tetrahydrocyclopenta[d]imidazol-2-yl)methyl)-2′,3′-dihydrospiro[azetidine-3,1′-indene]-1-carboxylate103a (0.1 g, 0.26 mmol) was dissolved in 2 mL DMSO, 4-bromobutyl acetate(62 mg, 0.32 mmol), cesium carbonate (0.17 g, 0.53 mmol) were added, thereaction mixture was stirred for 3 h at 80′C. The reaction solution wascooled to r.t., 30 mL water was added, extracted with EA (20 mL×3),organic phases were combined and washed in sequence with water (20mL×2), saturated sodium chloride solution (20 mL×2), dried overanhydrous sodium sulfate, filtered, the filtrate was concentrated underreduced pressure to obtain yellow oil. 2 mL 1M NaOH aqueous solution wasadded to dissolve, stirring for 1 h at r.t. 30 mL water was added intothe reaction solution, the mixture was extracted with EA (30 mL×2),organic phases were combined and washed with saturated sodium chloridesolution (20 mL×2), dried over anhydrous sodium sulfate, filtered, thefiltrate was concentrated under reduced pressure, preparative HPLC wasused to purify and the target product isopropyl1′-((1-(4-hydroxybutyl)-1,4,5,6-tetrahydrocyclopenta[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate103 (21 mg, white solid) was given, yield: 14.99%.

MS m/z (ESI): 453.3 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 7.62 (d, J=7.5 Hz, 1H), 7.28 (t, J=8.0 Hz,1H), 7.16 (t, J=8.0 Hz, 1H), 7.08 (d, J=8.0 Hz, 1H), 4.99 (s, 2H),4.96-4.91 (m, 1H), 4.34 (d, J=8.5 Hz, 2H), 4.16 (d, J=7.5 Hz, 2H), 4.01(t, J=7.3 Hz, 2H), 3.53 (t, J=6.3 Hz, 2H), 2.70 (t, J=6.5 Hz, 2H),2.60-2.52 (m, 2H), 2.51-2.42 (m, 2H), 1.74-1.66 (m, 2H), 1.54-1.44 (m,2H), 1.29 (d, J=6.0 Hz, 6H).

Embodiment 104 Ethyl2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-1,4,5,6-tetrahydrocyclopenta[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate

Step 1 Ethyl2′-oxo-1′-((1,4,5,6-tetrahydrocyclopenta[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate

Ethyl 2′-oxo-1′-(2-ethoxy)spiro[azetidine-3,3′-indoline]-1-carboxylate104a (1 g, 3.47 mmol) was dissolved in 10 mL ethanol,2-hydroxycyclopentane-2-enone (0.34 g, 3.47 mmol), ammonium acetate(1.34 g, 17.34 mmol) were added, and the reaction mixture was stirredfor 7 h at 80° C. The reaction solution was concentrated under reducedpressure, 100 mL saturated sodium carbonate aqueous solution was added,extracted with EA (100 mL×3), organic phases were combined and washed insequence with water (100 mL×2), saturated sodium chloride solution (100mL×2), dried over anhydrous sodium sulfate, filtered, the filtrate wasconcentrated under reduced pressure, the residue was purified by silicagel column chromatography with eluting system C to obtain ethyl2′-oxo-1′-((1,4,5,6-tetrahydrocyclopenta[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate104b (200 mg, yellow solid), yield: 15.74%.

¹H NMR (400 MHz, CD₃OD) δ 7.62 (d, J=7.3 Hz, 1H), 7.29-7.23 (m, 1H),7.19-7.12 (m, 1H), 6.83 (d, J=7.8 Hz, 1H), 4.93 (s, 2H), 4.39 (d, J=8.3Hz, 2H), 4.18 (q, J=7.0 Hz, 4H), 2.70-2.50 (m, 4H), 2.50-2.39 (m, 2H),1.29 (t, J=7.2 Hz, 3H).

Step 2 Ethyl2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-1,4,5,6-tetrahydrocyclopenta[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate

Ethyl2′-oxo-1′-((1,4,5,6-tetrahydrocyclopenta[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate104b (0.2 g, 0.55 mmol) was dissolved in 10 mL DMF,4-bromo-1,1,1-trifluorobutane (0.10 g, 0.55 mmol), cenium carbonate(0.36 g, 1.09 mmol) were added, stirring for 1 h at 80′C. The reactionsolution was cooled to r.t., 30 mL water was added, extracted with EA(20 mL×3), organic phases were combined and washed in sequence withwater (20 mL×2), saturated sodium chloride solution (20 mL×2), driedover anhydrous sodium sulfate, filtered, the filtrate was concentratedunder reduced pressure, preparative HPLC was used to purify and thetarget product ethyl2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-1,4,5,6-tetrahydrocyclopenta[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate104 (90 mg, white solid) was given, yield: 34.6%.

MS m/z (ESI): 477.3 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 7.65 (d, J=7.28 Hz, 1H), 7.30 (d, J=7.78 Hz,1H), 7.22-7.16 (m, 1H), 7.13 (d, J=7.78 Hz, 1H), 5.03 (s, 2H), 4.37 (d,J=8.28 Hz, 2H), 4.24-4.15 (m, 4H), 4.11 (t, J=7.40 Hz, 2H), 2.72 (t,J=6.78 Hz, 2H), 2.60 (d, J=6.27 Hz, 2H), 2.54-2.44 (m, 2H), 2.29-2.13(m, 2H), 1.91 (br. s., 2H), 1.31 (t, J=7.03 Hz, 3H).

Embodiment 1051-Isobutyryl-1′-((1-(4,4,4-trifluorobutyl)-1,4,5,6-tetrahydrocyclopenta[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one

Step 1 1-Isobutyrylspiro[azetidine-3,3′-indoline]-2′-one

tert-Butyl 2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate 105a (6.0g, 21.87 mmol) was dissolved in 50 mL DCM, trifluoroacetic acid (22.5 g,197.3 mmol) was added, stirring for 16 h at r.t. The reaction solutionwas concentrated under reduced pressure to obtain black oil. 25 mL DCM,TEA (7.86 g, 77.72 mmol) were added, isobutyryl chloride (2.8 g, 26.25mmol) was added at 0° C., stirring for 4 h at r.t. 100 mL water wasadded, the mixture was extracted with DCM (80 mL×3), organic phases werecombined and washed in sequence with water (80 mL×2), saturated sodiumchloride solution (80 mL×2), dried over anhydrous sodium sulfate,filtered, the filtrate was concentrated under reduced pressure, theresidue was purified with silica gel column chromatography with elutingsystem C to obtain 1-isobutyrylspiro[azetidine-3,3′-indoline]-2′-one105b (4.2 g, yellow solid), yield: 78.1%.

¹H NMR (400 MHz, CDCl₃) δ 7.68-7.62 (m, 1H), 7.41-7.32 (m, 1H),7.30-7.27 (m, 1H), 7.21-7.15 (m, 1H), 4.33 (d, J=8.03 Hz, 1H), 4.30 (d,J=8.03 Hz, 1H), 4.18 (d, J=8.03 Hz, 1H), 4.10 (d, J=8.03 Hz, 1H),2.50-2.40 (m, 1H), 1.70 (d, J=8.03 Hz, 6H).

Step 21′-(2,2-Diethoxy)-1-isobutyrylspiro[azetidine-3,3′-indoline]-2′-one

1-Isobutyrylspiro[azetidine-3,3′-indoline]-2′-one 105b (4.2 g, 17.1mmol) was dissolved in 20 mL DMF, 2-bromo-1,1-diethoxyl-ethane (3.37 g,17.1 mmol), cesium carbonate (9.30 g, 28.54 mmol), potassium iodide(0.24 g, 1.43 mmol) were added, stirring for 16 h at 90° C. The reactionsolution was cooled to r.t., 100 mL water was added, extracted with DCM(80 mL×3), organic phases were combined and washed in sequence withwater (80 mL×2), saturated sodium chloride solution (80 mL×2), driedover anhydrous sodium sulfate, filtered, the filtrate was concentratedunder reduced pressure, the residue was purified with silica gel columnchromatography with eluting system C to obtain1′-(2,2-diethoxy)-1-isobutyrylspiro[azetidine-3,3′-indoline]-2′-one 105c(4.2 g, yellow oil), yield: 67.0%.

¹H NMR (400 MHz, CDCl₃) δ 7.68-7.62 (m, 1H) 7.41-7.32 (m, 1H) 7.30-7.27(m, 1H) 7.21-7.15 (m, 1H) 4.70 (d, J=8.03 Hz, 1H) 4.60 (d, J=8.03 Hz,1H) 4.50 (d, J=8.03 Hz, 1H) 4.45 (d, J=8.03 Hz, 1H) 4.40 (d, J=8.03 Hz,3H) 3.80-3.60 (m, 2H) 3.50-3.40 (m, 2H) 2.50-2.40 (m, 1H) 1.17 (t, J=7.2Hz, 6H) 1.16 (t, J=7.2 Hz, 6H).

Step 32-(1-Isobutyryl-2′-oxospiro[azetidine-3,3′-indoline]-1′-yl)acetaldehyde

1′-(2,2-Diethoxy)-1-isobutyrylspiro[azetidine-3,3′-indoline]-2′-one 105c(3.50 g, 9.71 mmol) was dissolved in 30 mL DCM, 10 mL trifluoroaceticacid was added at 0° C., stirring for 2 h at r.t. 30 mL saturated sodiumcarbonate aqueous solution was added, the mixture was extracted with EA(20 mL×3), organic phases were combined and washed in sequence withwater (20 mL×2), saturated sodium chloride solution (20 mL×2), driedover anhydrous sodium sulfate, filtered, the filtrate was concentratedunder reduced pressure to obtain the crude product1′-(2,2-diethoxy)-1-isobutyrylspiro[azetidine-3,3′-indoline]-2′-one 105d(3.0 g, dark brown oil).

Step 41-Isobutyryl-1′-((1,4,5,6-tetrahydrocyclopenta[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one

1′-(2,2-diethoxy)-1-isobutyrylspiro[azetidine-3,3′-indoline]-2′-one 105d(3.21 g, 11.21 mmol) was dissolved in 50 mL ethanol,2-hydroxylcyclopentane-2-enone (1 g, 10.19 mmol), ammonium acetate (3.93g, 50.95 mmol) were added, the reaction mixture was stirred for 7 h at80° C. The reaction solution was concentrated under reduced pressure,100 mL saturated sodium carbonate aqueous solution was added, extractedwith EA (100 mL×3), organic phases were combined and washed in sequencewith water (100 mL×2), saturated sodium chloride solution (100 mL×2),dried over anhydrous sodium sulfate, filtered, the filtrate wasconcentrated under reduced pressure, the residue was purified withsilica gel column chromatography with eluting system C to obtain1-isobutyryl-1′-((1,4,5,6-tetrahydrocyclopenta[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one105e (500 mg, yellow solid), yield: 11.44%.

¹H NMR (400 MHz, CDCl₃) δ 7.48 (d, J=7.28 Hz, 1H), 7.34 (d, J=7.28 Hz,1H), 7.31-7.26 (m, 1H), 7.19-7.12 (m, 1H), 4.91 (d, J=11.04 Hz, 2H),4.57 (d, J=8.03 Hz, 1H), 4.41 (d, J=9.29 Hz, 1H), 4.29 (d, J=8.03 Hz,1H), 4.16 (d, J=9.54 Hz, 1H), 2.66-2.59 (m, 4H), 2.53 (td, J=6.78, 13.55Hz, 1H), 2.47-2.39 (m, 2H), 1.19 (d, J=6.78 Hz, 6H).

Step 51-Isobutyryl-1′-((1-(4,4,4-trifluorobutyl)-1,4,5,6-tetrahydrocyclopenta[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one

1-Isobutyryl-1′-((1,4,5,6-tetrahydrocyclopenta[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one105e (0.2 g, 0.55 mmol) was dissolved in 10 mL DMF,4-bromo-1,1,1-trifluorobutane (0.12 g, 0.60 mmol), cesium carbonate(0.36 g, 1.10 mmol) were added, stirring for 1 h at 80′C. The reactionsolution was cooled to r.t., 30 mL water was added, extracted with EA(20 mL×3), organic phases were combined and washed in sequence withwater (20 mL×2), saturated sodium chloride solution (20 mL×2), driedover anhydrous sodium sulfate, filtered, the filtrate was concentratedunder reduced pressure, preparative HPLC was used to purify and thetarget product1-isobutyryl-1′-((1-(4,4,4-trifluorobutyl)-1,4,5,6-tetrahydrocyclopenta[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one105 (100 mg, yellow solid) was given, yield: 38.0%.

MS m/z (ESI): 475.2 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 7.64 (d, J=7.28 Hz, 1H), 7.35-7.28 (m, 1H),7.23-7.17 (m, 1H), 7.14 (d, J=8.03 Hz, 1H), 5.03 (s, 2H), 4.59 (d,J=8.78 Hz, 1H), 4.48 (d, J=8.78 Hz, 1H), 4.35 (d, J=9.79 Hz, 1H), 4.18(d, J=9.79 Hz, 1H), 4.12 (t, J=7.53 Hz, 2H), 2.72 (t, J=6.78 Hz, 2H),2.69-2.56 (m, 3H), 2.50 (d, J=6.27 Hz, 2H), 2.31-2.13 (m, 2H), 1.99-1.85(m, 2H), 1.18 (d, J=7.03 Hz, 6H).

Embodiment 1061-(Methylsulfonyl)-1′-((1-(4,4,4-trifluorobutyl)-1,4,5,6-tetrahydrocyclopenta[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one

Step 1 1-(Methylsulfonyl)spiro[azetidine-3,3′-indoline]-2′-one

tert-Butyl 2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate 106a (12.0g, 43.75 mmol) was dissolved in 50 mL DCM, trifluoroacetic acid (22.5 g,197.3 mmol) was added, stirring for 16 h at r.t. The reaction solutionwas concentrated under reduced pressure to obtain black oil. 25 mL DCM,TEA (7.86 g, 77.72 mmol) were added, methanesulfonyl chloride (2.67 g,23.32 mmol) was added at 0° C., 50 mL water was added, the mixture wasextracted with DCM (80 mL×3), organic phases were combined and washed insequence with water (80 mL×2), saturated sodium chloride solution (80mL×2), dried over anhydrous sodium sulfate, filtered, the filtrate wasconcentrated under reduced pressure, the residue was purified by silicagel column chromatography with eluting system C to obtain1-(methylsulfonyl)spiro[azetidine-3,3′-indoline]-2′-one 106b (4.2 g,yellow solid), yield: 77.1%.

¹H NMR (400 MHz, CD₃OD) δ7.68-7.62 (m, 1H), 7.41-7.32 (m, 1H), 7.30-7.27(m, 1H), 7.21-7.15 (m, 1H), 4.33 (d, J=8.03 Hz, 2H), 4.18 (d, J=8.03 Hz,2H), 3.13 (s, 3H).

Step 21′-(2,2-Diethoxy)-1-(methylsulfonyl)spiro[azetidine-3,3′-indoline]-2′-one

1-(Methylsulfonyl)spiro[azetidine-3,3′-indoline]-2′-one 106b (3.6 g,14.27 mmol) was dissolved in 20 mL DMF, 2-bromo-1,1-diethoxyl-ethane(3.37 g, 17.12 mmol), cesium carbonate (9.30 g, 28.54 mmol), potassiumiodide (0.24 g, 1.43 mmol) were added, stirring for 16 h at 90° C. Thereaction solution was cooled to r.t., 100 mL water was added, extractedwith EA (100 mL×3), organic phases were combined and washed in sequencewith water (100 mL×2), saturated sodium chloride solution (100 mL×2),dried over anhydrous sodium sulfate, filtered, the filtrate wasconcentrated under reduced pressure, the residue by purified with silicagel column chromatography with elution system C to obtain1′-(2,2-diethoxy)-1-(methylsulfonyl)spiro[azetidine-3,3′-indoline]-2′-one106c (4.2 g, yellow oil), yield: 75.89%.

¹H NMR (400 MHz, CDCl₃) δ7.68-7.62 (m, 1H), 7.41-7.32 (m, 1H), 7.30-7.27(m, 1H), 7.21-7.15 (m, 1H), 4.70 (s, 1H), 4.31 (d, J=8.03 Hz, 2H), 4.33(d, J=8.03 Hz, 2H), 4.18 (d, J=8.03 Hz, 2H), 3.80-3.60 (m, 2H),3.50-3.30 (m, 2H), 3.13 (s, 3H), 1.16 (t, J=8.03 Hz, 6H).

Step 32-(1-(Methylsulfonyl)-2′-oxospiro[azetidine-3,3′-indoline]-1′-yl)acetaldehyde

1′-(2,2-Diethoxy)-1-(methylsulfonyl)spiro[azetidine-3,3′-indoline]-2′-one106c (4.2 g, 11.4 mmol) was dissolved in 20 mL DCM and 8 mL H₂O,trifluoroacetic acid (31.0 g, 271.9 mmol) was added dropwise at 0° C.,stirring for 2 h at r.t. Sodium carbonate was added to adjust pH to 9,the mixture was extracted with DCM (80 mL×3), organic phases werecombined and washed in sequence with water (80 mL×2), saturated sodiumchloride solution (80 mL×2), dried over anhydrous sodium sulfate,filtered, the filtrate was concentrated under reduced pressure to obtainthe crude product2-(1-(methylsulfonyl)-2′-oxospiro[azetidine-3,3′-indoline]-1′-yl)acetaldehyde106d (3.2 g, yellow solid).

Step 41-(Methylsulfonyl)-1′-((1,4,5,6-tetrahydrocyclopenta[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one

2-(1-(Methylsulfonyl)-2′-oxospiro[azetidine-3,3′-indoline]-1′-yl)acetaldehyde106d (3.1 g, 10.53 mmol) was dissolved in 25 mL ethanol,2-hydroxylcyclopentane-2-enone (1.24 g, 12.64 mmol), ammonium acetate(4.06 g, 52.65 mmol) were added, and the reaction mixture was stirredfor 8 h at 80° C. The reaction solution was concentrated under reducedpressure, 100 mL saturated sodium carbonate aqueous solution was added,extracted with EA (100 mL×3), organic phases were combined and washed insequence with water (100 mL×2), saturated sodium chloride solution (100mL×2), dried over anhydrous sodium sulfate, filtered, the filtrate wasconcentrated under reduced pressure, the residue was purified by silicagel column chromatography with elution system C to obtain1-(methylsulfonyl)-1′-((1,4,5,6-tetrahydrocyclopenta[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one106e (420 mg, yellow solid), yield: 8.57%.

¹H NMR (400 MHz, CDCl₃) δ7.68-7.62 (m, 1H), 7.41-7.32 (m, 1H), 7.30-7.27(m, 1H), 7.21-7.15 (m, 1H), 4.90 (s, 2H), 4.33 (d, J=8.03 Hz, 2H), 4.18(d, J=8.03 Hz, 2H), 4.15-4.05 (m, 1H), 3.08 (s, 3H), 2.68-2.58 (m, 3H),2.48-2.39 (m, 2H).

Step 51-(Methylsulfonyl)-1′-((1-(4,4,4-trifluorobutyl)-1,4,5,6-tetrahydrocyclopenta[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one

1-(Methylsulfonyl)-1′-((1,4,5,6-tetrahydrocyclopenta[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one106e (0.2 g, 0.54 mmol) was dissolved in 5 mL DMF,4-bromo-1,1,1-trifluorobutane (0.12 g, 0.64 mmol), cesium carbonate(0.35 g, 1.07 mmol) and potassium iodide (8.9 mg, 0.05 mmol) were added,stirring for 8 h at 90° C. The reaction solution was cooled to r.t., 30mL water was added, extracted with EA (20 mL×3), organic phases werecombined and washed in sequence with water (20 mL×2), saturated sodiumchloride solution (20 mL×2), dried over anhydrous sodium sulfate,filtered, the filtrate was concentrated under reduced pressure,preparative HPLC was used to purify and the target product1-(methylsulfonyl)-1′-((1-(4,4,4-trifluorobutyl)-1,4,5,6-tetrahydrocyclopenta[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one106 (42 mg, white solid) was given, yield: 15.56%.

MS m/z (ESI): 483.2 [M+1]

¹H NMR (400 MHz, CD₃OD) δ7.75-7.69 (m, 1H), 7.36-7.28 (m, 1H), 7.25-7.18(m, 1H), 7.14-7.07 (m, 1H), 5.00 (br. s., 2H), 4.84-4.78 (m, 1H),4.43-4.34 (m, 2H), 4.18-4.08 (m, 3H), 3.15 (s, 3H), 2.76-2.68 (m, 2H),2.64-2.55 (m, 2H), 2.54-2.44 (m, 2H), 2.30-2.17 (m, 2H), 1.99-1.89 (m,2H).

Embodiment 107 Isopropyl 1′-((1-(but-3-en-1-yl)-4, 5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-6′-chloro-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate

Step 1 Ethyl 4,5,6,7-tetrahydro-1H-benzo[d]imidazole-2-carboxylate

Cyclohexane-1,2-dione 107a (200.00 g, 1.78 mol) and formyl methylformate were dissolved in 2.00 L ethanol, ammonium acetate (687.5 g,3.57 mol) was added, stirring for 12 h at 90° C. The reaction solutionwas filtered and concentrated under reduced pressure, the residue waspurified with silica gel column chromatography with eluting system C toobtain ethyl2′-oxo-1′-((4,5,6,7-tetrahydrocyclopenta[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate107b (48.00 g, white solid), yield: 13.61%.

¹H NMR (400 MHz, METHANOL-d4) δ 4.35 (q, J=7.1 Hz, 2H), 2.65-2.55 (m.,4H), 1.84-1.73 (m, 4H), 1.37 (t, J=7.2 Hz, 3H).

Step 2 Ethyl1-(but-3-en-1-yl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazole-2-carboxylate

Ethyl 4,5,6,7-tetrahydro-1H-benzo[d]imidazole-2-carboxylate 107b (1.00g, 5.15 mmol) was dissolved in 8 mL anhydrous DMF, 4-bromobutyl-1-ene(1.06 g, 7.85 mmol), cesium carbonate (3.36 g, 10.30 mmol), potassiumiodide (85.49 mg, 515.00 μmol) were added in sequence, stirring for 2 hat 90′C. The reaction solution was cooled to r.t., 100 mL EA was added,washed in sequence with water (100 mL×2) and saturated sodium chlorideaqueous solution (100 mL), dried over anhydrous sodium sulfate,filtered, the filtrate was concentrated under reduced pressure to obtainthe crude product ethyl1-(but-3-en-1-yl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazole-2-carboxylate107c (1.2 g, yellow oil).

Step 3(1-(But-3-en-1-yl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methanol

Lithium aluminum hydride (596.57 mg, 15.72 mmol) was suspended in 10 mLanhydrous THF, ethyl1-(but-3-en-1-yl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazole-2-carboxylate107c (1.30 g, 5.24 mmol) in 10 mL THF was slowly added dropwise under anice-bath condition, and during the period of addition, the temperatureof the reaction solution was no more than 5° C. After stirring for 1 hat r.t., ice-water was added to quench the reaction under an ice-bathcondition, the reaction solution was filtered and the filtrate wasconcentrated under reduced pressure, the residue was purified by silicagel column chromatography with eluting system C to obtain(1-(but-3-en-1-yl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methanol107d (450 mg, white solid).

¹H NMR (400 MHz, CD₃OD) δ 5.90-5.65 (m, 1H), 4.99-5.30 (m, 2H), 4.63 (s,2H), 3.89-4.06 (m, 2H), 2.55-2.45 (m, 6H), 1.83-1.82 (m, 4H).

Step 4 Isopropyl 1′-((1-(but-3-en-1-yl)-4, 5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-6′-chloro-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate

(1-(But-3-en-1-yl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methanol(100.00 mg, 0.48 mmol) was dissolved in 5 mL anhydrous THF, isopropyl6′-chloro-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate 107d(171.45 mg, 0.58 mmol) and triphenyl phosphine (152.58 mg, 0.58 mmol)were added in sequence, then diisopropyl azodicarboxylate (117.63 mg,0.58 mmol) was added under an ice-bath condition. After stirring for 16h at r.t., the reaction solution was concentrated under reducedpressure, 30 mL water was added, extracted with EA (30 mL×2), organicphases were combined and washed in sequence with water (30 mL×3),saturated sodium chloride solution (30 mL×2), dried over anhydroussodium sulfate, filtered, the filtrate was concentrated under reducedpressure, preparative HPLC was used to purify and the target productisopropyl1′-((1-(but-3-en-1-yl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-6′-chloro-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate107 (30 mg, white solid) was given, yield: 12.81%.

MS m/z (ESI): 483.3 [M+1]

¹H NMR (400 MHz, MeOD) δ 7.62 (d, J=8.0 Hz, 1H), 7.17 (d, J=8.0 Hz, 1H),7.09 (s, 1H), 5.85-5.73 (m, 2H), 5.12-5.02 (m, 3H), 4.37-4.26 (m, 3H),4.22-4.12 (m, 3H), 4.09-3.96 (m, 3H), 2.61-2.47 (m, 2H), 2.43-2.30 (m,2H), 1.90-1.77 (m, 4H), 1.30 (d, J=6.27 Hz, 6H).

Embodiment 108 Isopropyl2′-oxo-1′-((7-oxo-1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate

Step 1 Isopropyl2′-oxo-1′-((7-oxo-4,5,6,7-tetrahydro-1H-benzo[d]azetidin-2-yl)methyl)spiro[imidazol-3,3′-indoline]-1-carboxylate

Isopropyl2′-oxo-1′-((4,5,6,7-tetrahydro-1H-benzo[d]azetidin-2-yl)methyl)spiro[imidazol-3,3′-indoline]-1-carboxylate108a (1.00 g, 2.54 mmol) was dissolved in 20 mL acetic acid and 20 mLwater, ammonium ceric nitrate (8.34 g, 15.21 mmol) was added, stirringfor 2 h at r.t. 30 mL water was added into the reaction mixture, themixture was extracted with EA (30 mL×3), organic phases were combinedand washed in sequence with water (30 mL×3), saturated sodium chloridesolution (30 mL×2), dried over anhydrous sodium sulfate, filtered, thefiltrate was concentrated under reduced pressure, the residue waspurified by silica gel column chromatography with eluting system C toobtain isopropyl2′-oxo-1′-((7-oxo-4,5,6,7-tetrahydro-1H-benzo[d]azetidine-2-yl)methyl)spiro[imidazol-3,3′-indoline]-1-carboxylate108b (300 mg, yellow solid), yield: 28.92%.

¹H NMR (400 MHz, CDCl₃) δ 7.58 (d, J=7.3 Hz, 1H), 7.37-7.30 (m, 1H),7.21-7.14 (m, 2H), 7.03 (br. s., 1H), 5.14-4.85 (m, 3H), 4.43 (d, J=7.8Hz, 2H), 4.18-4.12 (m, 2H), 2.85 (t, J=6.0 Hz, 2H), 2.52 (t, J=6.0 Hz,2H), 2.22-2.12 (m, 2H), 1.28-1.26 (m, 6H).

Step 2 Isopropyl2′-oxo-1′-((7-oxo-1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate

Isopropyl2′-oxo-1′-((7-oxo-4,5,6,7-tetrahydro-1H-benzo[d]azetidine-2-yl)methyl)spiro[imidazol-3,3′-indoline]-1-carboxylate108b (298.17 mg, 0.73 mmol) and 4-bromo-1,1,1-trifluorobutane (139.42mg, 0.73 mmol) were dissolved in 20 mL anhydrous DMF, cesium carbonate(475.70 mg, 1.46 mmol) was added, stirring for 4 h at 80° C. 30 mL waterwas added, the mixture was extracted with EA (30 mL×3), organic phaseswere combined and washed in sequence with water (30 mL×3), saturatedsodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate,filtered, the filtrate was concentrated under reduced pressure,preparative HPLC was used to purify and the target product isopropyl2′-oxo-1′-((7-oxo-1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate108 (60 mg, white solid) was given, yield: 28.92%.

MS m/z (ESI): 541.2 [M+23]

¹H NMR (400 MHz, MeOD) δ7.65 (d, J=7.3 Hz, 1H), 7.31 (t, J=7.6 Hz, 1H),7.20 (t, J=7.6 Hz, 1H), 7.02 (d, J=7.8 Hz, 1H), 5.09 (s, 2H), 4.95-4.94(m, 1H), 4.46 (t, J2=7.8 Hz, 2H), 4.35 (d, J=8.5 Hz, 2H), 4.16 (d, J=8.3Hz, 2H), 2.76 (t, J=6.0 Hz, 2H), 2.52 (t, J=6.3 Hz, 2H), 2.30-2.29 (m,2H), 2.17-2.05 (m, 2H), 1.96 (m, 2H), 1.29 (d, J=6.3 Hz, 6H).

Embodiment 109 Isopropyl1′-((7-hydroxy-1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate

Step 1 Isopropyl1′-((7-hydroxy-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate

Isopropyl2′-oxo-1′-((7-oxo-4,5,6,7-tetrahydro-1H-benzo[d]azetidine-2-yl)methyl)spiro[imidazol-3,3′-indoline]-1-carboxylate109a (600 mg, 1.47 mmol) was dissolved in 10 mL methanol, sodiumborohydride (166.83 mg, 4.41 mmol) was added, stirring for 12 h at r.t.50 mL water was added, the mixture was extracted with DCM (50 mL×3),organic phases were combined and washed in sequence with water (50mL×3), saturated sodium chloride solution (50 mL×2), dried overanhydrous sodium sulfate, filtered, the filtrate was concentrated underreduced pressure, the residue was purified by silica gel columnchromatography with eluting system C to obtain the crude productisopropyl1′-((7-hydroxy-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate1109b (360 mg, yellow solid).

Step 2 Isopropyl1′-((7-hydroxy-1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate

Isopropyl1′-((7-hydroxy-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate109b (360 mg, 0.877 mmol) and 4-bromo-1,1,1-trifluorobutane (335.01 mg,1.75 mmol) were dissolved in 10 mL anhydrous DMF, cesium carbonate(571.51 mg, 1.75 mmol) was added, stirring for 2 h at 80° C. 50 mL waterwas added, the mixture was extracted with EA (50 mL×3), organic phaseswere combined and washed in sequence with water (50 mL×3), saturatedsodium chloride solution (50 mL×2), dried over anhydrous sodium sulfate,filtered, the filtrate was concentrated under reduced pressure,preparative HPLC was used to purify and a pair of enantiomers 109 wasseparated by SFC, isopropyl1′-((7-hydroxy-1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate,(10 mg, white solid), yield: 28.92% and (12 mg, white solid), yield:28.92%, respectively.

MS m/z (ESI): 521.3 [M+1]

¹H NMR (400 MHz, MeOD) δ7.65 (d, J=7.3 Hz, 1H), 7.31 (t, J=7.6 Hz, 1H),7.20 (t, J=7.6 Hz, 1H), 7.02 (d, J=7.8 Hz, 1H), 5.09 (s, 2H), 4.95-4.94(m, 1H), 4.46 (t, J2=7.8 Hz, 2H), 4.35 (d, J=8.5 Hz, 2H), 4.16 (d, J=8.3Hz, 2H), 2.76 (t, J=6.0 Hz, 2H), 2.52 (t, J=6.3 Hz, 2H), 2.30-2.29 (m,2H), 2.17-2.05 (m, 2H), 1.96 (m, 2H), 1.29 (d, J=6.3 Hz, 6H).

Embodiment 110 Ethyl1′-((4-methyl-1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate

Step 1 Ethyl1′-((7-methyl-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate

3-Methylcyclohexane-1,2-dione 110a (0.52 g, 4.16 mmol) was dissolved in30 mL ethanol, ethyl2′-oxo-1′-(2-ethoxy)spiro[azetidine-3,3′-indoline]-1-carboxylate (1.2 g,4.16 mmol) and ammonium acetate (1.6 g, 20.8 mmol) were added, stirringfor 8 h at 80° C. The reaction solution was concentrated under reducedpressure, 100 mL saturated sodium carbonate aqueous solution was added,extracted with EA (100 mL×3), organic phases were combined and washed insequence with water (100 mL×2), saturated sodium chloride solution (100mL×2), dried over anhydrous sodium sulfate, filtered, the filtrate wasconcentrated under reduced pressure, the residue was purified by silicagel column chromatography with eluting system C to obtain ethyl1′-((7-methyl-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate110b (1.1 g, yellow solid), yield: 67.70%.

¹H NMR (400 MHz, CDCl₃) δ 7.53 (d, J=7.53 Hz, 1H), 7.37-7.25 (m, 2H),7.20-7.11 (m, 1H), 4.97-4.84 (m, 2H), 4.41 (dd, J=3.01, 8.28 Hz, 2H),4.20 (q, J=7.19 Hz, 2H), 4.15-4.10 (m, 2H), 2.49 (t, J=5.40 Hz, 2H),1.98-1.82 (m, 2H), 1.73-1.57 (m, 1H), 1.42-1.25 (m, 5H), 1.20 (d, J=7.03Hz, 3H).

Step 2 Ethyl1′-((4-methyl-1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate

Ethyl1′-((7-methyl-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate110b (0.2 g, 0.51 mmol) was dissolved in 10 mL DMF,4-bromo-1,1,1-trifluorobutane (0.11 g, 0.56 mmol), cesium carbonate(0.33 g, 1.01 mmol) were added, stirring for 1 h at 80′C. The reactionsolution was cooled to r.t., 30 mL water was added, extracted with EA(20 mL×3), organic phases were combined and washed in sequence withwater (20 mL×2), saturated sodium chloride solution (20 mL×2), driedover anhydrous sodium sulfate, filtered, the filtrate was concentratedunder reduced pressure, the preparative HPLC was used to purify and thetarget product ethyl1′-((4-methyl-1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate110 (100 mg, white solid) was given, yield: 38.3%.

MS m/z (ESI): 505.5 [M+1]

¹H NMR (400 MHz, CD₃OD) δ 7.64 (d, J=7.28 Hz, 1H), 7.29 (d, J=7.78 Hz,1H), 7.16-7.22 (m, 1H), 7.13 (d, J=8.03 Hz, 1H), 5.02 (d, J=14.56 Hz,2H), 4.37 (d, J=7.78 Hz, 2H), 4.20 (q, J=7.03 Hz, 4H), 4.04 (t, J=7.91Hz, 2H), 2.66-2.79 (m, 1H), 2.46-2.58 (m, 2H), 2.25 (dd, J=10.67, 16.44Hz, 2H), 1.90-2.02 (m, 2H), 1.68-1.87 (m, 3H), 1.38-1.48 (m, 1H), 1.31(t, J=7.03 Hz, 3H), 1.17-1.26 (m, 3H).

Experiment 1: In Vitro Assessment

RSV long CPE assay

Experimental Objective:

Detect EC₅₀ and CC₅₀ values of anti RSV respiratory tract viruscompounds through the cytopathic effect assay.

Experimental Materials:

Cell lines: Hep2

Virus strain: RSV respiratory tract virus (A long strain)

Cell culture medium (DMEM/F12, Gibco#11330, add 10% serum Gibco#16140,and 1% penicillin-streptomycin (penicillin 5000 IU/mL, streptomycin 10mg/mL), Gibco#15140)

Trypsin (Gibco#12605010)

PBS (Thermo#SH30264.01)

Trypan blue (Cat. Invitrogen#15250061)

CCK-8 (Dojindo#CK04-20)

CO2 incubator, Thermo 240 I

Multidrop, Thermo POD 810 Plate Assembler, Labcyte Scepter HandheldAutomated Cell Counter, Millipore Microplate Spectrophotometer,Molecular Device.

Experimental Procedure and Method:

A) Cell Vaccination (Cell Hep2)

1) absorb the culture medium of cell culture, clean with PBS 10 mL;

2) add preheated trypsin into a cleaned flask, revolve the flask to makeit evenly covered by trypsin. And then suck it up, and placed into 37°C., 5% CO₂ incubator to digest;

3) 10˜15 mL culture medium was used to suspend cells each T150, absorb0.1 mL and then dilute it 2 times counted by trypan blue solution;

4) dilute cells to 5×10⁴/mL with the culture medium, the diluted cellswas added into Corning 384 plate (Cat. 3701) (30 μL/hole, 1500cells/hole) with automatic liquid separator (Scientific Thermo). Thecell plate was centrifugated (300 rpm) to make the cells adherent to thewall, placed into a 37° C., 5% CO₂ incubator overnight.

B) Compound Sampling

1) the compound in 100% DMSO underwent a semi logarithmic dilution, thenwas added to the cell plate with a Echo liquid handler. Ensure that thefinal concentration of DMSO was 1%;

EC₅₀ (μM) CC₅₀ (μM) 50-0.07 μM (8 points semi 100-0.14 μM (8 points semilogarithmic dilution) logarithmic dilution)

2) Cell-control hole: no compound and viruse were added; virus-controlhole: no compound was added.

c) Virus Inoculation:

dilute RSV viruses to 100 TCID50/30 L with medium cultured with 4° C.cells, and then add the diluted viruses to a cell plate (30 μL/hole)with Multidrop® automatic liquid distributor, and then placed into a 37°C., 5% CO₂ culture incubator for 5 days.

d) Cytopathy Detection:

1) after 5 days, observe the pathological change in each hole. Undernormal condition, there is no pathological change in the cell-controlhole, and complete pathological change in the virus-control hole;

2) add CCK-8 (Dojindo-CK04-20, 6 μL/hole) to 384 well plate withMultidrop® automatic liquid distributor;

3) place the plate at a 37° C., 5% CO₂ culture incubator for 3˜4 h, readthe absorbance value with SPECTRA max 340PC_Molecular device at 450 nmand 630 nm;

4) analysis data.

The results of the experiment are shown in Table 1:

TABLE 1 Experimental results of CPE assay EC₅₀/CC₅₀ Test sample(compound obtained CPE assay EC₅₀/CC₅₀(μM) from the Embodiment) EC50CC50 BMS433771 A >100 Embodiment 62 A >100 Embodiment 63 A >100Embodiment 64 A >100 Embodiment 65 A >100 Embodiment 66 A >100Embodiment 67 B >100 Embodiment68 B >100 Embodiment 69 A >100 Embodiment70 A >100 Embodiment 71 B >100 Embodiment 72 A >100 Embodiment 73 A >100Embodiment 74 A >100 Embodiment 75 A >100 Embodiment 76 A >100Embodiment 77 A >100 Embodiment 78 A >100 Embodiment 79 A >100Embodiment 80 A >100 Embodiment 81 A >100 Embodiment 82 A >100Embodiment 83 A >100 Embodiment 84 A >100 Embodiment 85 A >100Embodiment 86 A >100 Embodiment 87 A >100 Embodiment 88 A >100Embodiment 89 A >100 Embodiment 90 A >100 Embodiment 91 A >100Embodiment 92 A >100 Embodiment 93 A >100 Embodiment 94 A >100Embodiment 95 A >100 Embodiment 96 A >100 Embodiment 97 A >100Embodiment 98 A >100 Embodiment 99 A >100 Embodiment 100 A >100Embodiment 101 — >100 Embodiment 102 A >100 Embodiment 103 A >100Embodiment 104 A >100 Embodiment 105 A >100 Embodiment 106 A >100Embodiment 107 A >100 Embodiment 108 B >100 Embodiment 109 B >100Embodiment 110 B >100 Note: EC₅₀ shows the in vitro activity of themolecule for anti-respiratory virus. According to the degree of theactivity, two ranges are divided: A (EC₅₀ < 0.1 μM); B (0.1 μM < EC₅₀ <1 μM). The numeric value of CC₅₀ indicates the degree of the toxicity ofthe molecule in vitro. Conclusion: compared with BMS433771, the in vitroactivity and toxicity of the compound of the present invention aresimilar or even better.

1.-15. (canceled)
 16. A process for treating respiratory syncytial virusinfection in a subject thereof, comprising administering an effectiveamount of a compound having formula (XI) or a pharmaceutical acceptablesalt thereof to the subject;

wherein, optionally, the compound or the pharmaceutical acceptable saltthereof containing one or more chiral centers each of X₁, X₂ and X₄independently represents CH, or substituted CH; X₃ represents CH, N, orsubstituted CH; R₂ is a C₁₋₆ alkyl group or a C₂₋₆ alkenyl group thatare optionally substituted by 0-3 halogen atoms, CN or OH, and whereinoptionally one of —C(═O)—, —S(═O)— or —S(═O)₂— is inserted into thechain of the alkyl or alkenyl group; Z represents C═O; each of U or Vindependently represents CH₂; L represents NH, N-Boc, N—C(═O)OCH(CH₃)₂,N—C(═O)CH(CH₃)₂, N—C(O)—R₀₂, N—S(O)₂R₂, or N—C(O)—OR₀₂, wherein R₀₂ is ahydrogen, unsubstituted C₁₋₆ linear alkyl or C₃₋₅ cycloalkyl group, orC₁₋₆ linear alkyl or C₃₋₅ cycloalkyl group substituted by hydroxyl,halogen, or amino groups; one of D₁₋₄ is —C(R_(d1))(R_(d2))— or —C(═O)—,and the remaining three are CH₂; and each of R_(d1) and R_(d2) isindependently selected from H, OH, or CH₃.
 17. A process for treatingrespiratory syncytial virus infection in a subject thereof, comprisingadministering an effective amount of a compound of the following formulaor a pharmaceutical acceptable salt thereof to the subject;

wherein each of X₁, X₂, and X₄ independently represents CH, orsubstituted CH; X₃ represents CH, N, or substituted CH; R₂ is a C₁₋₆alkyl group or a C₂₋₆ alkenyl group that are optionally substituted by0-3 halogen atoms, CN or OH, and wherein optionally one of —C(═O)—,—S(═O)— or —S(═O)₂— is inserted into the chain of the alkyl or alkenylgroup; Z represents C═O; one of D₁₋₄ is —C(R_(d1))(R_(d2))— or —C(═O)—,and the remaining three are CH₂; each of R_(d1) and R_(d2) isindependently selected from H, OH, or CH₃.
 18. A process according toclaim 16, wherein each of R_(d1) and R_(d2) is independently selectedfrom H or CH₃.
 19. A process according to claim 16, wherein both ofR_(d1) and R_(d2) are CH₃.
 20. A process according to claim 16, whereinR₂ is selected from the following groups:

and R₄ is H.
 21. A process according to claim 16, wherein the compoundis selected from the group consisting of the following compounds: 62)Isopropyl1′-((1-(4-hydroxybutyl)-4,5,6,7-tetrahydro-H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate;64) Isopropyl1′-((1-(4,4-difluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate;65) Isopropyl2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-spiro[azetidine-3,3′-indoline]-1-carboxylate;66) Isopropyl2′-oxo-1′-((1-(2,2,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate;67) Isopropyl1′-((1-(2,2-difluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate;68) Isopropyl1′-((1-(3-methyl-2-oxobutyl)-4,5,6,7-tetrahydro-H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate;69) Isopropyl1′-((1-(2,2-difluoro-3-methylbutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate;70) (Z)-isopropyl1′-((1-(2-fluoro-3-methylbut-1-en-1-yl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate;71) Isopropyl1′-((1-(2-fluoro-3-methylbut-2-en-1-yl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate;72) Ethyl1′-((1-isopentyl-4,5,6,7-tetrahydro-H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate;73) Ethyl1′-((1-(3-fluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate;74) Ethyl1′-((1-(3-cyanopropyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate;75) Ethyl2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate;76) Ethyl1′-((1-(3-(methylsulfonyl)propyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate;77) Cyclopentyl1′-((1-(3-hydroxybutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate;78) Isopropyl5′-bromo-1′-((1-(4-hydroxybutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate;79) Isopropyl5′-bromo-2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate;80) Isopropyl5′-chloro-2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate;81) Isopropyl6′-chloro-2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate;82) Isopropyl6′-fluoro-2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate;83) Ethyl6′-fluoro-2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate;84)1-(Cyclopropanecarbonyl)-6′-fluoro-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one;85) Isopropyl4′-chloro-1′-((1-(4-hydroxybutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate;86) Isopropyl4′-chloro-2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate;87) Ethyl2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-1′,2′-dihydrospiro[azetidine-3,3′-pyrrolo[2,3-c]pyridine]-1-carboxylate;88) Isopropyl2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-1′,2′-dihydrospiro[azetidine-3,3′-pyrrolo[2,3-c]pyridine]-1-carboxylate;89)1-(Cyclopropanecarbonyl)-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-pyrrolo[2,3-c]pyridin]-2′(1′H)-one;90)2′-Oxo-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carbaldehyde;91)1-(1-Methylcyclopropanecarbonyl)-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-pyrrole[2,3-c]pyridine]-2′-one;92)1-Acetyl-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one;93)1-(Cyclopropanecarbonyl)-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one;94)1-Propionyl-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one;95)1-Isobutyryl-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one;96)1-(2,2-Difluoroacetyl)-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one;97)1-(Methylsulfonyl)-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one;98)1-(Cyclopropylsulfonyl)-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one;99)1-(Isopropylsulfonyl)-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one;102) Isopropyl2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-1,4,5,6-tetrahydrocyclopenta[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate;103) Isopropyl1′-((1-(4-hydroxybutyl)-1,4,5,6-tetrahydrocyclopenta[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate;104) Ethyl2′-oxo-1′-((1-(4,4,4-trifluorobutyl)-1,4,5,6-tetrahydrocyclopenta[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate;105)1-Isobutyryl-1′-((1-(4,4,4-trifluorobutyl)-1,4,5,6-tetrahydrocyclopenta[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one;106)1-(Methylsulfonyl)-1′-((1-(4,4,4-trifluorobutyl)-1,4,5,6-tetrahydrocyclopenta[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-2′-one;107) Isopropyl1′-((1-(but-3-en-1-yl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-6′-chloro-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate;108) Isopropyl2′-oxo-1′-((7-oxo-1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indoline]-1-carboxylate;109) Isopropyl1′-((7-hydroxy-1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate;and 110) Ethyl1′-((4-methyl-1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate.22. A process according to claim 17, wherein the compound is1′-((1-(4-Hydroxybutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[cyclopropane-1,3′-indoline]-2′-one.23. A process according to claim 17, wherein R₂ is substituted by 1-3halogen atoms which are independently fluorine, chlorine, bromine oriodine.
 24. A process according to claim 17, wherein R₂ is selectedfrom;

and R₄ is selected from H.
 24. A process according to claim 17, whereinsubstituted CH in X₁, X₂, X₃, or X₄ is CH wherein the H is replaced byhalogen.
 25. A process according to claim 24, wherein the halogen isindependently selected from fluorine, chlorine, bromine or iodine.
 26. Aprocess according to claim 16, wherein R₂ is substituted by 1-3 halogenatoms which are independently fluorine, chlorine, bromine or iodine. 27.A process according to claim 16, wherein substituted CH in X₁, X₂, X₃,or X₄ is CH wherein the H is replaced by halogen.
 28. A processaccording to claim 27, wherein the halogen is independently selectedfrom fluorine, chlorine, bromine or iodine.
 29. A process according toclaim 17, wherein each of R_(d1) and R_(d2) is independently H or CH₃.30. A process according to claim 17, wherein both of R_(d1) and R_(d2)are CH₃.
 31. A process according to claim 16, wherein L is selectedfrom; —C(═O)OC(CH₃)₃, —C(═O)OCH(CH₃)₂, —C(═O)CH(CH₃)₂, —S(═O)₂CH₃,


32. A process according to claim 16, wherein R₀₂ is substituted byhalogen atoms which are independently fluorine, chlorine, bromine oriodine.